Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1392&sort=abstract
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=abstract", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1405&sort=abstract", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1393&sort=abstract", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1391&sort=abstract" }, "data": [ { "type": "Grant", "id": "982", "attributes": { "award_id": "2107902", "title": "The Role of Tetrel Bonding in the Reaction Mechanism of Methyltransferases", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)" ], "program_reference_codes": [], "program_officials": [ { "id": 2387, "first_name": "Herman", "last_name": "Sintim", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-07-01", "end_date": "2024-06-30", "award_amount": 519000, "principal_investigator": { "id": 2389, "first_name": "Raymond", "last_name": "Trievel", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 169, "ror": "", "name": "Regents of the University of Michigan - Ann Arbor", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 2388, "first_name": "Allison", "last_name": "Stelling", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 169, "ror": "", "name": "Regents of the University of Michigan - Ann Arbor", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Drs. Raymond Trievel of the University of Michigan - Ann Arbor and Allison Stelling of UT-Dallas are studying an important category of enzymes known as methyltransferases. Methyltransferases are ubiquitous enzymes that play fundamental roles in the metabolism of numerous biological molecules, as well as in cell signaling and gene regulation through methylation of proteins, DNA, and RNA. In addition, methyltransferases have been implicated in numerous diseases, rendering them important targets for the design of new modulators to study their functional significance and signaling roles in biology and their dysfunction in abnormal biology or disease (relevant to cancer, cardiovascular disease, some neurological disorders, and microbial viral infections including COVID-19). Recent studies have revealed that the methyl transfer reaction catalyzed by these enzymes occurs through an unconventional type of interaction called a tetrel bond. The existence of tetrel bonds in biological macromolecules has only recently been discovered, and the contributions of these interactions to biological processes, particularly methyl transfer, remain poorly understood. The goal of this project is to characterize the functions of the tetrel bonds in methyltransferases using experimental and computational approaches. The knowledge derived from these studies will potentially inform the development of new methyltransferase linhibitors. This project will engage both undergraduate and graduate students in research in the fields of biochemistry, biophysics, structural biology and spectroscopy, affording multi-disciplinary training at the chemistry-biology interface.Methylation is a ubiquitous reaction in biology that plays a central role in the metabolism of many biological molecules, including amino acids, carbohydrates, lipids, hormones, and metabolites. In addition, methylation represents a prominent covalent modification in proteins, DNA, and RNA, which has been implicated in signal transduction and gene regulation. Most methylation reactions are catalyzed by S-adenosylmethionine (AdoMet)-dependent methyltransferases via an SN2 transfer of the AdoMet methyl group to the acceptor substrate. A recent survey of crystal structures of methyltransferases bound to AdoMet and various ligands has revealed that the AdoMet methyl group engages in tetrel bonding, a type of sigma antibonding orbital interaction similar to halogen bonding. Prior computational studies utilizing small molecule models have demonstrated that tetrel bonding between the methyl carbon atom and the nucleophilic atom represents an intermediate preceding the transition state in the SN2 reaction pathway. The discovery of tetrel bonding between the AdoMet methyl carbon atom and various ligands in methyltransferase active sites implies that this interaction is fundamental to the catalytic mechanism of these enzymes. Building on these observations, the aims of this proposal are to: 1) determine the functions of AdoMet methyl tetrel bonding in catalysis and 2) characterize the effects of methyl tetrel bonding on the AdoMet methyl vibrational modes. The functional importance of these interactions will be investigated in detail using a model methyltransferase and an interdisciplinary approach combining biochemistry, spectroscopy, crystallography, and computational chemistry. Taken together, these studies aim to elucidate the mechanism by which tetrel bonding between the AdoMet methyl group and the nucleophile facilitates methyl transfer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "1037", "attributes": { "award_id": "2108690", "title": "Phase-Sensitive Chiral Sum Frequency Generation Vibrational Spectroscopy for Probing Protein Hydration at Aqueous Interfaces", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)" ], "program_reference_codes": [], "program_officials": [ { "id": 2546, "first_name": "Herman", "last_name": "Sintim", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-08-01", "end_date": "2024-07-31", "award_amount": 290000, "principal_investigator": { "id": 2547, "first_name": "E. Chui-Ying", "last_name": "Yan", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 452, "ror": "https://ror.org/03v76x132", "name": "Yale University", "address": "", "city": "", "state": "CT", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 452, "ror": "https://ror.org/03v76x132", "name": "Yale University", "address": "", "city": "", "state": "CT", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professor Elsa Chui-Ying Yan of Yale University is studying protein interactions with water on surfaces by developing a new optical method. Proteins are molecular machineries that carry out biological functions. Many of them are situated on cell surfaces for critical life processes, such as cell communication, cell adhesion, and immunological response. These proteins are excellent targets for drug design and the recent success in developing the COVID-19 vaccine is an example. In industries, protein stability upon interactions with surfaces can greatly impact product quality, such as food packaging and drug delivery systems. Also, proteins are incorporated on surfaces for making biosensors and molecular devices. Therefore, being able to predict protein behaviors on various surfaces can help advance fundamental knowledge and develope new drugs and materials. Nonetheless, proteins on surfaces cannot function by themselves. Not only do they interact with the surface materials (e.g., cell membrane and plastic packages), they are also integrated with surrounding water molecules. These water molecules determine protein structures and functions, and thus must be considered to fully understand and predict protein behaviors. Professor Yan will develop a new optical technique with unprecedented selectivity for detecting water molecules and their interactions with proteins on surfaces. Combining experimental and computational methods, Professor Yan will develop approaches to generate detailed descriptions of these water molecules interacting with various types of proteins on surfaces. Professor Yan will provide training opportunities to students at various levels in conducting scientific research and organize students to reach out to a neighborhood high school to support their STEM education program and hold panel discussions on STEM career opportunities. The project will develop external heterodyne chiral vibrational sum frequency (SFG) generation spectroscopy to probe protein hydration at interfaces. This method is expected to have the advantages of being in situ, real-time, and label-free. More importantly, it will provide unique selectivity to water molecules surrounding proteins that are in folded chiral structures without interference of background signals from interfacial and bulk water. The project will construct an external heterodyne SFG spectrometer to acquire water O-H stretching spectra at the air/water interface in the presence of proteins that with attention to their secondary, tertiary, and quaternary structures. Molecular dynamics (MD) models being constructed at the interface will be used to simulate the phase-resolved chiral SFG spectra. The comparison of the experimental and computational spectra in conjunction with analyses of the MD trajectories will allow for extraction of information about topology and local interactions of water molecules around the proteins. Finally, the combined experimental and computational approaches will be used to investigate changes in water structures during protein denaturation on surfaces.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "15157", "attributes": { "award_id": "2427912", "title": "Collaborative Research: Nucleobase-Modified PNA for Sequence Selective Triple-Helical Recognition of Non-Coding RNA", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)", "Chemistry of Life Processes" ], "program_reference_codes": [], "program_officials": [ { "id": 31733, "first_name": "John C.", "last_name": "Jewett", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-08-15", "end_date": null, "award_amount": 360000, "principal_investigator": { "id": 31734, "first_name": "James", "last_name": "MacKay", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 494, "ror": "https://ror.org/01y0mgq54", "name": "Elizabethtown College", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professors Eriks Rozners of SUNY at Binghamton and James A. MacKay of Elizabethtown College are studying new methods for molecular recognition of biologically significant non-coding RNA. With the onset of biochemical technologies such as CRISPR-Cas9 and the challenges associated with emerging pathogens such as the SARS-CoV-2 virus, RNA chemistry and biochemistry is at the forefront of research. Less than 2% of DNA encodes for functional proteins, while over 70% of DNA is transcribed into RNA. The non-coding RNAs play important yet not fully understood roles in regulation of biological processes. Selective recognition, imaging, and functional regulation of such RNAs will be highly useful for fundamental science and practical biotechnology applications. The project is focused on uncovering new ways for targeting double-stranded RNA (dsRNA), which is a long-standing problem and practical limitation in RNA biochemistry. The impact of the project will be broadened by expanding interdisciplinary collaborative research across traditional institutional boundaries and fostering the training and development of a diverse, globally competitive STEM workforce through research and mentoring activities. The collaboration continues a partnership that has established a bridge for Elizabethtown College (a primarily undergraduate institution) students, including women, minorities, and first-generation college students, for transitioning from undergraduate to advanced graduate studies at a research university. Work will continue toward improving STEM education of undergraduate and graduate students and offer unique training for graduate students and postdoctoral researchers interested in faculty positions at primarily undergraduate institutions. <br/><br/>The development of sequence-selective RNA binders is important for understanding the biochemistry of non-coding RNAs and may strongly impact fundamental RNA biology and practical applications in biotechnology and synthetic biology. The collaborative study will focus on development of new peptide nucleic acid (PNA) nucleobases capable of recognition of any sequence of dsRNA. Objective 1 develops nucleobases that could improve pi-pi stacking of the PNA strand in PNA-dsRNA triplexes. Objective 2 develops extended nucleobases that could recognize the entire Hoogsteen face of Watson-Crick base pairs of dsRNA. The properties of the new PNAs will be optimized using molecular modelling and dynamics simulations and synthetic organic chemistry. If successful, the project could allow molecular recognition of any sequence of dsRNA and enable a variety of applications such as imaging and functional control of regulatory RNA, designer riboswitches for synthetic biology, and inhibition of biologically important RNA for fundamental studies.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "15158", "attributes": { "award_id": "2427911", "title": "Collaborative Research: Nucleobase-Modified PNA for Sequence Selective Triple-Helical Recognition of Non-Coding RNA", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)", "Chemistry of Life Processes" ], "program_reference_codes": [], "program_officials": [ { "id": 31733, "first_name": "John C.", "last_name": "Jewett", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2024-08-15", "end_date": null, "award_amount": 465000, "principal_investigator": { "id": 2425, "first_name": "Eriks", "last_name": "Rozners", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 384, "ror": "", "name": "SUNY at Binghamton", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 384, "ror": "", "name": "SUNY at Binghamton", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Chemistry of Life Processes (CLP) program in the Division of Chemistry, Professors Eriks Rozners of SUNY at Binghamton and James A. MacKay of Elizabethtown College are studying new methods for molecular recognition of biologically significant non-coding RNA. With the onset of biochemical technologies such as CRISPR-Cas9 and the challenges associated with emerging pathogens such as the SARS-CoV-2 virus, RNA chemistry and biochemistry is at the forefront of research. Less than 2% of DNA encodes for functional proteins, while over 70% of DNA is transcribed into RNA. The non-coding RNAs play important yet not fully understood roles in regulation of biological processes. Selective recognition, imaging, and functional regulation of such RNAs will be highly useful for fundamental science and practical biotechnology applications. The project is focused on uncovering new ways for targeting double-stranded RNA (dsRNA), which is a long-standing problem and practical limitation in RNA biochemistry. The impact of the project will be broadened by expanding interdisciplinary collaborative research across traditional institutional boundaries and fostering the training and development of a diverse, globally competitive STEM workforce through research and mentoring activities. The collaboration continues a partnership that has established a bridge for Elizabethtown College (a primarily undergraduate institution) students, including women, minorities, and first-generation college students, for transitioning from undergraduate to advanced graduate studies at a research university. Work will continue toward improving STEM education of undergraduate and graduate students and offer unique training for graduate students and postdoctoral researchers interested in faculty positions at primarily undergraduate institutions. <br/><br/>The development of sequence-selective RNA binders is important for understanding the biochemistry of non-coding RNAs and may strongly impact fundamental RNA biology and practical applications in biotechnology and synthetic biology. The collaborative study will focus on development of new peptide nucleic acid (PNA) nucleobases capable of recognition of any sequence of dsRNA. Objective 1 develops nucleobases that could improve pi-pi stacking of the PNA strand in PNA-dsRNA triplexes. Objective 2 develops extended nucleobases that could recognize the entire Hoogsteen face of Watson-Crick base pairs of dsRNA. The properties of the new PNAs will be optimized using molecular modelling and dynamics simulations and synthetic organic chemistry. If successful, the project could allow molecular recognition of any sequence of dsRNA and enable a variety of applications such as imaging and functional control of regulatory RNA, designer riboswitches for synthetic biology, and inhibition of biologically important RNA for fundamental studies.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "993", "attributes": { "award_id": "2107900", "title": "Collaborative Research: Nucleobase-Modified PNA for Sequence Selective Triple-Helical Recognition of Non-Coding RNA", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)" ], "program_reference_codes": [], "program_officials": [ { "id": 2424, "first_name": "Herman", "last_name": "Sintim", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-08-01", "end_date": "2024-07-31", "award_amount": 468000, "principal_investigator": { "id": 2425, "first_name": "Eriks", "last_name": "Rozners", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 384, "ror": "", "name": "SUNY at Binghamton", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 384, "ror": "", "name": "SUNY at Binghamton", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors Eriks Rozners of SUNY Binghamton and James A. MacKay of Elizabethtown College are studying new methods for molecular recognition of biologically significant non-coding ribonucleic acid (RNA). With the onset of biochemical technologies such as CRISPR-Cas9 for DNA-editing, and the challenges associated with emerging pathogens such as the SARS-CoV-2 virus (novel coronavirus), RNA (ribonucleic acid) chemistry and biochemistry is at the forefront of research. We know that less than 2% of deoxyribonucleic acid (DNA) encodes for functional proteins, while over 70% of DNA is transcribed into RNA. The non-coding RNAs play important yet not fully understood roles in regulation of biological processes. Selective recognition, imaging, and functional regulation of such RNAs will be highly useful for fundamental science and practical applications in biotechnology. This project aims to establish new ways of targeting double-stranded RNA, which has been a long-standing problem and practical limitation in RNA biochemistry. Importantly, the project will be broader in its impact through expanding interdisciplinary collaborative research across traditional institutional boundaries and fostering the training and development of a diverse, globally competitive STEM (science, technology, engineering and mathematics) workforce through research and mentoring activities. The collaboration continues a 5 year partnership that has established a bridge for Elizabethtown College (a primarily undergraduate institution) students, especially women, minorities, and first generation college students for transitioning from undergraduate studies to advanced graduate studies at a research university. Work will contine toward improving STEM education of undergraduate and graduate students, and offer unique training for post-graduate students interested in exploring careers at a primarily undergraduate institution. The development of sequence-selective RNA binders is important for understanding the biochemistry of non-coding RNAs and may strongly impact fundamental RNA biology and practical applications in biotechnology and synthetic biology. This collaborative study will develop new derivatives of peptide nucleic acid (PNA) that are potentially capable of recognizing the entire Hoogsteen face of Watson-Crick base pairs of double-stranded RNA. This is to be achieved by development of new nucleobases and binding modes that place two anti-parallel PNA strands in the major groove, each hydrogen-bonding to their respective RNA strand. The properties of the new PNAs will be optimized using synthetic organic chemistry to promote recognition of diverse sequences of double-stranded RNA, which has the potential to solve a long-standing problem in molecular recognition of RNA. If successful, this research will enable a variety of applications, such as, imaging and functional control of regulatory RNA, designer riboswitches for synthetic biology, and inhibition of biologically important RNA for fundamental studies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "994", "attributes": { "award_id": "2107911", "title": "Collaborative Research: Nucleobase-Modified PNA for Sequence Selective Triple-Helical Recognition of Non-Coding RNA", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)" ], "program_reference_codes": [], "program_officials": [ { "id": 2426, "first_name": "Herman", "last_name": "Sintim", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2021-08-01", "end_date": "2024-07-31", "award_amount": 300000, "principal_investigator": { "id": 2427, "first_name": "James A", "last_name": "MacKay", "orcid": null, "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 494, "ror": "https://ror.org/01y0mgq54", "name": "Elizabethtown College", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 494, "ror": "https://ror.org/01y0mgq54", "name": "Elizabethtown College", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors Eriks Rozners of SUNY Binghamton and James A. MacKay of Elizabethtown College are studying new methods for molecular recognition of biologically significant non-coding ribonucleic acid (RNA). With the onset of biochemical technologies such as CRISPR-Cas9 for DNA-editing, and the challenges associated with emerging pathogens such as the SARS-CoV-2 virus (novel coronavirus), RNA (ribonucleic acid) chemistry and biochemistry is at the forefront of research. We know that less than 2% of deoxyribonucleic acid (DNA) encodes for functional proteins, while over 70% of DNA is transcribed into RNA. The non-coding RNAs play important yet not fully understood roles in regulation of biological processes. Selective recognition, imaging, and functional regulation of such RNAs will be highly useful for fundamental science and practical applications in biotechnology. This project aims to establish new ways of targeting double-stranded RNA, which has been a long-standing problem and practical limitation in RNA biochemistry. Importantly, the project will be broader in its impact through expanding interdisciplinary collaborative research across traditional institutional boundaries and fostering the training and development of a diverse, globally competitive STEM (science, technology, engineering and mathematics) workforce through research and mentoring activities. The collaboration continues a 5 year partnership that has established a bridge for Elizabethtown College (a primarily undergraduate institution) students, especially women, minorities, and first generation college students for transitioning from undergraduate studies to advanced graduate studies at a research university. Work will contine toward improving STEM education of undergraduate and graduate students, and offer unique training for post-graduate students interested in exploring careers at a primarily undergraduate institution. The development of sequence-selective RNA binders is important for understanding the biochemistry of non-coding RNAs and may strongly impact fundamental RNA biology and practical applications in biotechnology and synthetic biology. This collaborative study will develop new derivatives of peptide nucleic acid (PNA) that are potentially capable of recognizing the entire Hoogsteen face of Watson-Crick base pairs of double-stranded RNA. This is to be achieved by development of new nucleobases and binding modes that place two anti-parallel PNA strands in the major groove, each hydrogen-bonding to their respective RNA strand. The properties of the new PNAs will be optimized using synthetic organic chemistry to promote recognition of diverse sequences of double-stranded RNA, which has the potential to solve a long-standing problem in molecular recognition of RNA. If successful, this research will enable a variety of applications, such as, imaging and functional control of regulatory RNA, designer riboswitches for synthetic biology, and inhibition of biologically important RNA for fundamental studies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "11147", "attributes": { "award_id": "2238139", "title": "CAREER: The Lassa Virus Fusion Domain - A Cyclic Approach to Revealing the Molecular Chemistry behind Membrane Fusion", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)", "Chemistry of Life Processes" ], "program_reference_codes": [], "program_officials": [ { "id": 27135, "first_name": "Christine", "last_name": "Chow", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-04-01", "end_date": "2028-03-31", "award_amount": 820000, "principal_investigator": { "id": 27136, "first_name": "Jin Woo", "last_name": "Lee", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 297, "ror": "https://ror.org/047s2c258", "name": "University of Maryland, College Park", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the CLP program in the Division of Chemistry, Jin Woo Lee from the University of Maryland, College Park is studying the molecular chemistry behind the initiation of Lassa Virus (LASV) membrane fusion. LASV is a member of the Arenavirus family that is currently endemic to West Africa, and there is an increasing incidence of LASV infection reported worldwide. The pandemic potential of LASV has already been noted by the World Health Organization (WHO) in 2018, which stated that the virus requires urgent and prioritized research. Membrane fusion is a key component of the LASV lifecycle that allows the virus to deliver its genetic information into the target cell through a chemical process that is not well understood. The process is thought to be facilitated by specialized fusion machinery that undergoes structural transitions triggered by specific environmental conditions. One such example of this machinery is the fusion domain (FD), which is predominately associated with the initiation of membrane fusion. The research aims to identify, on a molecular level, exactly how the FD initiates the process of membrane fusion. Such information is often a prerequisite for novel therapeutic design that may serve to arrest the viral lifecycle and prevent and/or treat LASV infection. Simultaneously, an educational outreach program will be implemented focused on providing opportunities for incoming transfer students as well as local high school students to gain practical scientific research experience. The aim of the program is to improve both the retention and enrollment of students within the science, technology, engineering, and mathematics (STEM) fields.\n\nThe initiation of LASV membrane fusion relies on the FD, which resides within the viral glycoprotein found on the viral surface. This domain is well conserved across the Arenavirus family and is also structurally distinct, containing both an N-terminal fusion peptide (FP) and an internal fusion loop (FL). The overarching goal of the research is to understand how the underlying chemistry of the FD contributes to the initiation of membrane fusion. Specifically, the structural and functional roles of multiple fusogenic regions within the LASV FD and the impacts of environmental conditions will be examined. A cyclic approach will be employed utilizing solution nuclear magnetic resonance (NMR) spectroscopy to elucidate the structural rearrangement of the LASV FD. The NMR work will be complemented by thermodynamic and kinetic investigations through isothermal titration calorimetry (ITC) and in vitro lipid mixing fusion assays. The framework mentioned allows the investigation of the FD as both a peptide and within the context of the full viral glycoprotein. The latter requires a novel approach involving specific labeling and incorporation into a lipid bilayer, both of which will be implemented in order to provide more physiological relevance. Upon conclusion of the research, a major knowledge gap regarding LASV membrane fusion will be filled and a framework for studying other viral FDs will be established.\n\nThis award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "13051", "attributes": { "award_id": "2213353", "title": "LEAPS-MPS: Determining the Mechanisms by Which Alarmone Signaling in Clostridioides Difficile Differs From Tthat in other Bacteria", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Mathematical and Physical Sciences (MPS)", "OFFICE OF MULTIDISCIPLINARY AC" ], "program_reference_codes": [], "program_officials": [ { "id": 4073, "first_name": "Anne-Marie", "last_name": "Schmoltner", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2022-07-15", "end_date": null, "award_amount": 250000, "principal_investigator": { "id": 29051, "first_name": "Erin", "last_name": "Purcell", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 237, "ror": "", "name": "Old Dominion University Research Foundation", "address": "", "city": "", "state": "VA", "zip": "", "country": "United States", "approved": true }, "abstract": "With the support of the Mathematical and Physical Sciences Directorate and the Division of Chemistry, Professor Erin B. Purcell and her group at Old Dominion University will study nucleotide signal molecules known as ‘alarmones.’ Bacteria across diverse types respond to environmental stress by synthesizing different chemical species, such as tetraphosphate and pentaphosphate alarmones, to regulate survival mechanisms. Until recently, smaller triphosphate alarmones were thought to be degradation products of the larger signal molecules. However, it has recently been discovered that some bacteria synthesize triphosphate alarmones directly in addition to the tetra- and pentaphosphate signals. To date, the anaerobic spore-forming bacterium Clostridioides difficile is the only bacterium reported to synthesize triphosphate alarmones exclusively. Graduate and undergraduate trainees in the Purcell lab intend to determine how this organism’s alarmone synthesis and utilization differ from those in other bacteria. This project is expected to expand understanding of alarmone signaling and establish a paradigm for signaling by the triphosphate alarmone alone. This project will provide opportunities to train graduate and undergraduate researchers in foundational biochemistry techniques. Graduate researchers, mostly from underrepresented groups, will also gain experience as co-mentors of undergraduate trainees to nurture their leadership skills as future scientific leaders and role models.<br/><br/>The objectives of this project will be to determine the structural basis of this organism’s unique alarmone synthesis and the regulatory role played by the incompletely characterized triphosphate alarmone, pGpp. The Purcell group is especially interested in discovering which active site residues in the clostridial alarmone synthetase enzymes are involved in hydrolyzing phosphate bonds on its nucleotide substrates to generate pGpp. Successful implementation of this project will also determine whether clostridial alarmone hydrolases and alarmone-binding effectors can recognize the larger alarmones produced by nearby bacteria, potentially utilizing alarmones for intercellular and interspecies communication as well as intracellular signaling. This project has the potential to identify the genes and processes regulated by alarmone signaling in C. difficile to determine whether it uses its non-canonical alarmone in a conserved manner or whether the outputs of alarmone signaling pathways in this organism are also unique.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "12190", "attributes": { "award_id": "1R01HL167273-01A1", "title": "MAP2K1 AND MAP2K2 IN ACUTE LUNG INJURY AND RESOLUTION", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Heart Lung and Blood Institute (NHLBI)" ], "program_reference_codes": [], "program_officials": [ { "id": 22454, "first_name": "GUOFEI", "last_name": "Zhou", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2023-08-24", "end_date": "2027-07-31", "award_amount": 736534, "principal_investigator": { "id": 28059, "first_name": "ANNE M.", "last_name": "MANICONE", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 159, "ror": "https://ror.org/00cvxb145", "name": "University of Washington", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "With the surge of ARDS cases associated with SARS-CoV-2 infection, there is an urgent need to understand novel pathways involved in resolution of lung inflammation and injury to provide the basis for new therapeutic approaches. Studies comparing rodent and human lung injury gene expression signatures reveal conserved pathways, including MAPK/ERK activation during injury. More recently, we found a genetic polymorphism in MAP2K2 associates with death in ARDS, suggesting a biological role in ALI recovery. We demonstrated that MAP2K1/MAP2K2 (MEK1/MEK2) activation in macrophages promotes pro-inflammatory pathways and inhibits reparative ones, making it a potential target to manipulate macrophage phenotypes in ALI. In preclinical acute lung injury (ALI) models, inhibition of MEK1/MEK2 improves measures of ALI, including faster recovery of body weight, reduced pulmonary neutrophilia, and greater reparative macrophage activation. These results suggest that MEK pathways could be effective targets in ALI. To address the isoform and cell source driving this improvement in outcome, we generated mice deficient in MEK1 in myeloid cells (LysmCre+Mek1fl). These mice have no phenotype in naïve conditions, but experience 100% mortality with LPS-induced ALI using a moderate LPS dose from which all wild-type mice recover. These mice have a similar early inflammatory response to LPS but fail to turn off inflammation at later time-points. This phenotype can be completely rescued with IFNAR1 blockade, suggesting MEK1 suppression of type I interferon responses is critical for ALI resolution. We also found sustained MEK2/p-ERK activation in the absence of MEK1, suggesting that MEK1 is critical for MEK2 deactivation to promote ALI resolution. In support of this hypothesis, we found that mice lacking MEK2 globally or in the leukocytes compartment have faster ALI resolution. The proposed aims below outline our approach to identify how MEK isoforms work in concert to regulate myeloid cell responses to better define and target a novel regulatory pathway in ALI. In aim 1, we will determine MEK1 and MEK2 cell-specific roles and signaling pathways in ALI and test our will test our hypothesis that MEK1 is required to deactivate MEK2 in alveolar macrophages to promote resolution of lung inflammation. In aim 2, we plan to evaluate MEK1 and MEK2 interactions and mechanisms of MEK2 deactivation. We will use MEK1 mutants to test our hypothesis that MEK2 is deactivated by binding to pT292 MEK1, and we will determine how these mutants alter macrophage inflammatory (LPS) and reparative (IL-4) responses. In aim 3, we plan to test MEK1 and MEK2 degraders as therapeutics in murine models of ALI. We will test our hypothesis that MEK2-specific degradation will result in faster ALI resolution. These studies will advance our understanding of how the immune system stops inflammation and promotes ALI resolution, revealing new therapeutic targets and approaches that could be brought to the bedside.", "keywords": [ "Acceleration", "Acute Lung Injury", "Acute Respiratory Distress Syndrome", "Address", "Alveolar Macrophages", "Antibodies", "Automobile Driving", "Binding", "Biological", "Body Weight", "Cell Survival", "Cell physiology", "Cells", "Cessation of life", "Clinical", "Data", "Dependence", "Disease", "Dose", "Enterobacteria phage P1 Cre recombinase", "Extracellular Signal Regulated Kinases", "Gene Expression", "Gene Expression Profile", "Genetic Polymorphism", "Human", "IFNAR1 gene", "Immune system", "Impairment", "In Vitro", "Inflammation", "Inflammatory", "Inflammatory Response", "Injury", "Interferon Type I", "Interleukin-4", "KRP protein", "Leukocytes", "Lung", "MAP2K1 gene", "MAPK3 gene", "MEKs", "Macrophage Activation", "Measures", "Mitogen-Activated Protein Kinases", "Modeling", "Mus", "Myelogenous", "Myeloid Cells", "Neutrophil Infiltration", "Neutrophilia", "Outcome", "Pathway interactions", "Patients", "Phenotype", "Phosphorylation", "Phosphotransferases", "Process", "Protein Isoforms", "Protein Kinase", "Publishing", "Pulmonary Inflammation", "Recovery", "Regulation", "Regulatory Pathway", "Resolution", "Rodent", "Role", "Route", "SARS-CoV-2 infection", "Signal Pathway", "Signal Transduction", "Site", "Source", "Sterility", "Testing", "Therapeutic", "Time", "Toxic effect", "Translating", "Wild Type Mouse", "Work", "epithelial repair", "experience", "extracellular", "improved", "injured", "injury recovery", "lung injury", "macrophage", "mortality", "mouse model", "mutant", "new therapeutic target", "novel", "novel therapeutic intervention", "pre-clinical", "repaired", "response", "single-cell RNA sequencing", "wound healing" ], "approved": true } }, { "type": "Grant", "id": "1585", "attributes": { "award_id": "2029281", "title": "RAPID: Ecological Dynamics of Human Coronavirus", "funder": { "id": 3, "ror": "https://ror.org/021nxhr62", "name": "National Science Foundation", "approved": true }, "funder_divisions": [ "Biological Sciences (BIO)" ], "program_reference_codes": [ "096Z", "7465", "7914" ], "program_officials": [ { "id": 4151, "first_name": "David", "last_name": "Rockcliffe", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2020-05-01", "end_date": "2022-04-30", "award_amount": 200000, "principal_investigator": { "id": 4152, "first_name": "John", "last_name": "Yin", "orcid": "https://orcid.org/0000-0001-6146-0594", "emails": "[email protected]", "private_emails": "", "keywords": null, "approved": true, "websites": "['https://yin.discovery.wisc.edu/', 'https://news.wisc.edu/research-on-viral-junk-quicker-drug-testing-could-help-ou…', 'https://www.youtube.com/watch?v=0OI9_B76gN4&feature=youtu.be', 'https://www.youtube.com/watch?v=-4LCDNgaSPE']", "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 263, "ror": "", "name": "University of Wisconsin-Madison", "address": "", "city": "", "state": "WI", "zip": "", "country": "United States", "approved": true }, "abstract": "With the zoonotic spillover of coronavirus into humans and the rapid emergence of coronavirus disease (COVID-19), humanity faces its first global pandemic in more than a century. Current molecular, cellular and animal studies of the infectious agent, SARS-CoV-2, use purified virus stocks that ignore a more likely scenario which is that the natural infection spreads as a mixture of active and defective virus strains. This project is developing mathematical models and wet-lab experiments on human coronaviruses that highlight how ecological interactions between such strains and their host cells critically impact the dynamics of virus growth, spread and ultimately their ability to cause disease. The developed models account for the presence of defective virus strains. The broader impact of the results of this project would guide clinical and front-line researchers with direct access to patients, in exploring broader and deeper measures of the infection dynamics and in applying novel therapies. The project has potential to significantly impact the development of strategies that mitigate the pandemic. This project develops mathematical models and performs wet-lab experiments on human coronaviruses. The outcome will highlight how ecological interactions between strains and their host cells could critically impact the dynamics of virus growth, spread and ultimately their ability to cause disease. The project goals are to: (i) extract essential mechanisms and parameters of coronavirus intracellular growth from the literature, (ii) build mathematical models that account for the kinetics of viral entry, gene expression, genome replication and particle assembly in the absence and presence of defective interfering (DI) particles, and (iii) implement wet-lab experiments to demonstrate the emergence of DI particles from coronavirus cultures, activation immune cytokine signaling, and validate the intracellular kinetic models. This RAPID award is made by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biology, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.", "keywords": [], "approved": true } } ], "meta": { "pagination": { "page": 1392, "pages": 1405, "count": 14046 } } }