# data[].attributes.title
REPTOR: accelerating antibody discovery and improving hits with machine learning

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National Institute of General Medical Sciences (NIGMS)

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Antibody therapeutics are becoming increasingly important across a broad range of indications, yet their development requires discovery from a variety of difficult sources. Traditional technologies are over four decades old, while newer single-cell approaches for mining survivors are gaining traction in the wake of the SARS-Cov2 pandemic. However, all mainstream discovery approaches significantly limit the sampling of the in-vivo antibody immune response, thereby potentially missing important therapeutic candidates. Approaches to better deconvolute the antibody response with high-throughput sequencing technologies have begun to be applied for research uses. However, using these large-scale data to directly perform antibody discovery has remained elusive.  We aim to develop software to streamline the incorporation of high-throughput sequencing into the three mainstream discovery approaches, thereby reducing time and increasing discovery success rate. These software-enabled enhancements will cover high-throughput sequencing for hybridoma discovery, enhanced enrichment analysis for display methods, and simplified workflow analysis for popular single-cell methods. The same type of repertoire sequencing can then be used in a different context to improve candidate antibodies by leveraging the natural improvements the host individual’s immune system has already discovered. This expansion of existing candidates is enabled by the deep sequencing of antibody repertoires using next-generation sequencing technology that provides a window into the natural antibody evolution and optimization. These newly deep repertoires are able to be exploited by novel algorithms for analyzing the large antibody families produced, as well as advances in deep learning that enable large amounts of unlabeled data to be synthesized and used for model training to search both across antibody families for similarities, as well as within those families.

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Center for Multiscale Immune Systems Modeling

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National Institute of Allergy and Infectious Diseases (NIAID)

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The Center of Excellence (CoE) is a research initiative that brings together experts from various fields to develop innovative solutions for multi-scale modeling in infectious and immune-mediated disease (IID). The CoE consists of the: Administrative Core (AC), Community Development and Education Core (CDEC), Model and Data Sharing Core (MDSC), and three Research Projects (RP). Each component plays a crucial role. The AC serves as a central hub, connecting various entities, and plays a critical role in pivoting CoE resources during disease outbreaks. It administers the Opportunities Fund, supporting proposals from investigators across NIAID- sponsored modeling groups. The CDEC will develop educational resources, build communities of practice and learning, organize research experiences for graduate students and postdoctoral fellows, and set up document sharing facilities, messaging platforms, and a centralized website to facilitate knowledge sharing. The MDSC will develop an informatics infrastructure that enables seamless integration of data and models across different scales, facilitating more accurate predictions and informed decision-making. The RPs focus on bridging models of host-virus interactions across biological scales. RP1 models humoral defense against viral pathogens, using antibody-antigen molecular dynamics at the molecule scale to understand the constraints limiting the evolution of immune repertoires at the individual scale. RP2 models the immune cell as a target of viral infection, using agent-based models of lymphoid tissue at the cell scale to inform host-pathogen dynamics at the individual scale. RP3 models the interactions between individuals and populations, using agent based models of host-pathogen interactions at the individual scale to inform stochastic epidemic models at the population scale. The research focuses on modeling a set of clinically important viruses, including HIV-1, SARS-CoV-2, Epstein Barr Virus (EBV), and others. The models can be used to study disease pathogenesis, the effect of medical interventions, and disease transmission in heterogeneous population networks. Key strengths of the proposed CoE are (1) the ability to coordinate administrative approaches and technologies for the infectious disease modeling community; (2) a collaborative environment that encourages knowledge sharing, innovation, and the development of cutting- edge solutions; (3) balanced representation of the experimental and computational communities within each Core and RP; (4) extensive experience with IID modeling, team science, education, and community development; (5) robust informatics infrastructure for model and data sharing that already hosts large-scale NIH- funded projects; (6) exceptional strengths integrating generative deep learning with computational modeling in the MDSC and RPs, and (7) the importance of the proposed research to develop more accurate IID models that can inform public health policy and decision-making. The unique strengths of the proposed CoE make it an ideal platform for advancing IID research, developing innovative solutions to complex problems, and responding during infectious disease outbreaks, epidemics and pandemics.

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National Institute of Allergy and Infectious Disease

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United States National Institutes of Health

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Accelerating the translation of oligonucleotide therapeutics by enhancing delivery

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National Center for Advancing Translational Sciences (NCATS)

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Oligonucleotide therapeutics (ONTs) are poised to ignite a paradigm shift in what constitutes a “treatable” human disease. The FDA approval of life-changing ONTs like Spinraza (Ionis’ ASO therapy for spinal muscular atrophy), Onpattro (Alnylam’s siRNA therapy for hATTR amyloidosis), and the mRNA-based COVID-19 vaccines from Pfizer and Moderna that saved millions of lives demonstrate the profound potential impact ONTs can have on “undruggable” diseases. CRISPR-based editing strategies are now entering the clinic, with lipid nanoparticle-mediated delivery of mRNA encoding Cas9 variants offering an alternative to problematic viral vectors. Suppressor tRNAs that read through premature stop codons to restore proteins that were “lost in translation” are moving towards the clinic. Each of these ONTs faces a shared barrier to broad clinical translation: biological membranes. The large size (5-35 kD) and charged backbone of ONTs severely limits their ability to cross the plasma membrane. Even if the plasma membrane is crossed by promoting the endocytosis of the ONT, the endosomal membrane remains a highly effective barrier that prevents ONTs from reaching their targets in the cytosol and nucleus. Estimates are that only 1-3% of the ONT delivered to a patient reaches its target - the delivery stats are dismal for naked, ligand-conjugated, and LNP-encased ONTs. ONTs tend to accumulate in the liver, and most FDA-approved ONTs that are delivered systemically have liver targets. ONT conjugation to GalNAc, the ligand for the asialoglycoprotein receptor expressed on hepatocytes, improves delivery 30-fold. Other approved agents rely on local delivery to increase ONT exposure to a level sufficient to provide clinical value. However, not all tissues are suited for local delivery, many cell types with these tissues remain inaccessible to ONTs, and local delivery risks infection or damage to the target organ. There is thus a critical unmet need for strategies that improve the delivery of systemically administered ONTs to extrahepatic tissues. Until this need is met, a revolution in medical practice ushered in by nucleotide-based therapies will remain a dream unrealized. This proposal seeks a small molecule solution to the delivery problem. This strategy would be effective for multiple ONT platforms and disease agnostic. By drilling down on rigorous target validation from the outset, we hope to initiate a successful drug development program that takes the most direct path to the clinic. Our lead compounds diverge from status quo potentiators in that they dramatically increase ONT activity without causing endosomal damage, an effective, but prohibitively toxic, mode of action. The expected results would provide a solid foundation for funding a successful lead optimization program supported by target engagement assays and highlight the diseases most likely to rapidly realize the benefits of this approach.

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Clustered Regularly Interspaced Short Palindromic Repeats

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The 10th International Symposium on Middle Ear Mechanics in Research and Otology (MEMRO 2025)

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National Institute on Deafness and Other Communication Disorders (NIDCD)

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We are seeking partial support through this proposal to cover the expenses for the 10th International Meeting of the Middle Ear Mechanics in Research and Otology (MEMRO) 2025 conference, scheduled for June 2025 at the KU Leuven, in Belgium. In alignment with the objectives established at the inaugural MEMRO meeting in 1996, the purpose of this triennial event is to bring together experts in middle ear science and engineering with clinical otologists to facilitate an exchange of knowledge and ideas between these typically independent groups. Previous MEMRO meetings in Shanghai (2018) and Denmark (2015) each attracted approximately 200 participants from over 20 countries. The 2022 meeting had slightly fewer participants since scientists from many countries, including China, Japan, Australia, and others, that would normally attend the MEMRO meetings were still precluded from travel due to COVID restrictions. We expect the 10th edition to have a higher attendance. The 2025 meeting aims to continue promoting the free exchange of ideas between basic and clinical scientists and to establish a framework for innovative collaborative efforts to enhance our understanding of middle ear function, dysfunction, and repair. A primary goal of this meeting is to increase the diversity of attendees, with a particular focus on engaging otology residents and faculty by hosting a hands-on workshop on methods and technologies the day prior to the formal conference. Also many efforts have been made to increase the presence of underrepresented countries. We have promoted the conference on multiple occasions on other world conferences. We have representatives from all continents in the scientific committee. The 2025 MEMRO meeting is being organized by KU Leuven, Belgium's largest and highest-ranked university and is an excellent center for education, research and Innovation. Leuven is a vibrant city only 15 minutes by train from Brussels Airport allowing easy travel, and is rich in art, history, and architecture, offering attendees ample opportunities to experience this dynamic international city.

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This new application is to establish the North Texas Alzheimer’s Disease Research Center (NT-ADRC) which will serve North Texas, one of the most-populous catchment areas in the country. This application describes how we plan to build a unique and interconnected multidisciplinary center that will create an environment that enables and supports innovative research, training and eventually enhance the care and lives of those dealing with Alzheimer's Disease (AD) and related dementias (ADRD). It is built on a strong foundation of AD and ADRD research and will synergize and connect multiple AD/ADRD investigators and their programs at University of Texas (UT) Southwestern Medical Center, UT Dallas, and UT Arlington. The NT-ADRC will benefit from the strong institutional support to advance AD and ADRD research, our long history of studying cardiometabolic factors, particularly hypertension, in AD/ADRD, our recent expansion of the cutting-edge neuroimaging, informatics, machine learning, and artificial intelligence (ML/AI) capabilities in neurosciences, and the recruitment of multiple key leaders in the Neurocognitive space. The NT-ADRC thematic focus is on examining the roles and mechanisms of hypertension and other cardiometabolic factors in the early phases of AD/ADRD, developing innovative biomarkers for early detection, and identifying related therapeutic targets. We have an exceptional engagement in our diverse communities that is amplified by the participation of Parkland Health and its community ties. We also create novel ways to enhance inclusiveness in ADRD research particularly Lumbar Punctures acceptance and Brain Donation enrollment. These amplify the Center’s abilities to create a highly diverse UDS cohort representative of our diverse population as evidenced by our affiliated studies (Dallas Heart Study and the NIA-funded Post-COVID Neuro-Cognitive Manifestations in Older African Americans). The NT-ADRC Center addresses multiple elements in the National Alzheimer's Project Act (NAPA) and its Implementation Milestones by enabling ongoing and new research in the preclinical and prodromal stages centered around the discovery of novel disease mechanisms underlying the role of hypertension and other cardiometabolic factors in increasing the risk of AD/ADRD; implementing novel ML/AI approaches to biomarker developments; and paving the way for novel therapeutic developments. The NT- ADRC will enhance scientific and clinical collaborations by sharing of biosamples and data with local and national investigators, dissemination of research findings to professional and lay audiences and create education opportunities for researchers, clinicians, learners, and the general North Texas community focused on enhancing caregivers’ education and support. Our commitment to diversity, innovation and rigor to ADRD research will build a new local environment of cutting-edge research and training. It will also position us to make important contributions to the ADRC network and to advance the national agenda towards meeting the NAPA goals.

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Enhancing the utility of deer mice as an infectious disease model

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National Institute of Allergy and Infectious Diseases (NIAID)

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UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA

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UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA

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Deer mice (genus Peromyscus) are the most abundant mammals in North America. In biomedical research, their most prominent use is in the field of infectious diseases, because they are the natural reservoir of infectious agents such as Borrelia burgdorferi which causes Lyme disease, for Hantaviruses, Sin Nombre Virus, and SARS-CoV-2 that caused the COVID-19 pandemic. The University of South Carolina operates, for more than 40 years, the Peromyscus Genetic Stock Center (PGSC) that is charged with the mission of maintaining different stocks of Peromyscus, supplying them to outside investigators and exploiting deer mouse- related research. The present proposal addresses 3 major unmet needs of the Peromyscus community of researchers that impede the use of deer mice as a model and are related to the poor breeding program that does not enable rapid availability if deer mice to users, the lack of Peromyscus-specific antibodies, and the lack of readily access to breeding records for pedigree analyses. Here, we request funds to enhance the utility of deer mice as a model of relevance to NIAID’s interests by (1) strengthening the breeding capacities of the PGSC, (2) by developing specialized immunological reagents such as Peromyscus-specific antibodies, and (3) by curating our electronic databases and rendering them easily accessible to outside users. Plans for the project’s sustainability have been developed, and it is anticipated that upon completion it will be supported fully by the income generated.

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National Institute of Allergy and Infectious Disease

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United States National Institutes of Health

# data[].attributes.title
Targeting Immune Dysregulated Endotypes in Sepsis (TIDES)

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National Institute of General Medical Sciences (NIGMS)

# data[].attributes.abstract
/ ABSTRACT  Pediatric sepsis is the leading cause of death of hospitalized children worldwide. While sepsis is defined as life-threatening organ dysfunction that develops in the setting of immune dysregulation, optimal management of immune dysregulation in pediatric sepsis is a fundamental knowledge gap. A successful precision medicine approach to pediatric sepsis requires that we understand the molecular events that cause organ failure, which of these events are potentially reversible, and how to identify this reversible patient pathobiology in real-time. We recently identified features of cellular immune dysregulation in children with sepsis and used proteomics to define three molecular subphenotypes which predict the severity of organ failure and mortality. Reproducible, validated molecular sepsis subphenotypes are viable candidates for translation to clinical trials, as models based on clinical data and plasma proteins could be used to identify “treatable traits” in real-time for both prognostic and predictive enrichment. Our preliminary data also identifies a pathologic and potentially reversible role for STAT3 hyperactivation in our most severe sepsis subphenotype. The IL-6/JAK/STAT3 signaling pathway is a canonical inflammatory pathway associated with capillary leak, endothelial dysfunction, emergency granulopoiesis, and lymphocyte dysregulation. Selective and non-selective JAK inhibitors have been used clinically to treat COVID-19 ARDS and pediatric hemophagocytic lymphohistiocytosis (HLH). It is not known if JAK inhibition can reverse immune dysregulation in sepsis, despite its related pathobiology. We propose to address these current knowledge gaps by defining and validating molecular subphenotype that predicts sepsis severity and testing the reversibility of T cell STAT3 hyperactivation. The overall objectives of this application are to define and prospectively evaluate a model to identify prognostic molecular sepsis subphenotypes (Aim 1) and to determine the impact of ex vivo JAK/STAT inhibition to reduce immune dysregulation in pediatric patients with sepsis (Aim 2). My central hypothesis is that immune dysregulation in pediatric sepsis can be identified in the plasma proteome and reversed with targeted immunomodulation. By validating a model to prospectively identify prognostic molecular sepsis subphenotypes and determining the impact of JAK/STAT inhibition on immune dysregulation, this study will support a precision approach to immunomodulation in pediatric patients with sepsis. My long-term goal is to design precision approaches to immunomodulation in critically ill children as a translational critical care physician-scientist trained in computational human immunology. I am optimally situated to perform these studies given my background as a clinician, my experience in prospective cohort development and proteomic subphenotyping, and the strong mentorship and supportive environment at CHOP/UPenn. The K23 award will provide new skills in translational research and computational analysis, facilitating my development as an independent investigator with expertise in translational human immunology.

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Mentored Clinical Scientist Development Program

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Mentored Patient-Oriented Research Career Development Award

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The role of SARS-CoV-2-induced senescence in the development of Alzheimer's Disease

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National Institute of Neurological Disorders and Stroke (NINDS)

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SARS-CoV-2 has been associated with neurological symptoms, although there is no strong evidence of a direct viral infection in the brain. Recent reports indicate that SARS-CoV-2-induced systemic inflammation and the cleaved S1 subunit of the S protein remain detectable in patients with COVID-19 for months after diagnosis and may cause neurological manifestations. Also, COVID-19 tends to be more severe in older people, and although various biological responses change with aging, the induction of cellular senescence (SC) is predominant. New findings indicate that SARS-CoV-2 induces senescence in the lung epithelium with an exacerbated senescence- associated secretory phenotype (SASP) in response to the S1 subunit of the SARS-CoV-2 spike protein. Here, we will investigate how SARS-CoV-2 promotes CS in the brain and the role of SASP components in conveying senescence and promoting AD pathogenesis. Our preliminary data show that the S1 protein enters the systemic circulation and accumulates in the choroid plexus (CP) epithelium that expresses the ACE2 receptor. When S1 is combined with systemic inflammation, it induces a senescence-like phenotype in the brain of aged mice, initially restricted to epithelial cells in the CP, but it spreads to other brain regions, including the cortex and hippocampus, within a month. Transcriptome analysis in the brains of aged S1-challenged mice with systemic inflammation 30 days post S1 administration identified the "metabolic pathways," "pathways in neurodegeneration," and "Alzheimer's disease" among the top 10 enriched pathways. We also investigated how the S1 cleaved subunit induces cellular senescence (CS) in the choroid plexus epithelial cells when combined with systemic inflammation, and our results indicate that S1 induces dysfunction of the Nrf2-antioxidant response, which leads to accelerated CS when it is accompanied by LPS-induced ROS production. Most importantly, SASP analysis revealed the role of soluble factors SASP and EV-miRNA SASP components in conveying CS of neurons and regulating CS and AD pathways, respectively. Therefore, our goal is to explore whether miRNA replacement therapy can abrogate secondary SASP-induced senescence and AD pathogenesis and progression. Furthermore, analysis of postmortem brain sections and CSF from AD patients revealed the presence of CS markers in the CP long before the robust accumulation of β-amyloid and tau tangles in HPC, suggesting that CS may play an important role in Alzheimer's pathogenesis. Analysis of CSF from the early stages of AD also showed high levels of soluble SASP factors, which correlates well with the cellular senescent burden in the CP that produces the CSF. These findings prompted us to examine the relationship between CS and SARS-CoV-2 infection further and how it may increase the risk for AD. Our hypothesis is that SARS-CoV- 2-induced SASP in the CSF induces neuronal senescence and increases AD risk. Patients with severe COVID- 19 may be predisposed to develop AD later in life. These studies will allow us to identify better diagnostic markers and therapeutic targets and enable early intervention to prevent the development and progression of AD.

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2025 USUCGER Early Career Workshop for Geotechnical Faculty; Atlanta, Georgia; October 2025

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This award is to support participants to attend the third United States Universities Council on Geotechnical Education and Research (USUCGER) Early Career Workshop that will be held in October 2025 in collaboration with the Geosystems Engineering faculty at the Georgia Institute of Technology in Atlanta, Georgia. The workshop will be a 1.5-day event focused on issues that are impactful for the initiation of an academic career in today’s rapidly changing research and teaching environment with an academic context significantly impacted by the COVID-19 pandemic and the advent and prevalence of artificial intelligence across university campuses.    This workshop will bring together the newest generation of geotechnical engineering faculty to:  1) Facilitate research collaborations through formal presentations and informal discussions;  2) Identify best practices in research and teaching, with special attention to artificial intelligence in the laboratory and in the classroom;  3) Facilitate entrepreneurial thinking through sessions on research commercialization and technology transfer;  4) Facilitate mentoring, work-life balance, and human connection in a post COVID academic world;    The format of the workshop is designed to broaden perspective and widen access to new ways of thinking for early-career faculty as they embark on an academic career path. The workshop will focus on practical best methods that researchers and teachers can take back to their home institutions to help build the most solid foundation for a productive and innovative career. Outcomes of the workshop will include a post-workshop report hosted on a dedicated website managed by USUCGER, as well as the creation of a monthly “Office Hour with the Program Director” which will allow junior faculty to sign up for small group mentoring sessions with the CMMI program director. It is anticipated there will be 10 one-hour sessions of 6-8 junior faculty who will be able to ask questions about a range of topics pertaining to researching with NSF and life as a junior faculty member.    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.

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SARS-CoV-2 tropism and immunomodulation in salivary gland

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National Institute of Dental and Craniofacial Research (NIDCR)

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SARS-CoV-2 has been detected in a variety of human tissues, including the salivary gland. While its behavior in  the respiratory tract has been widely studied, relatively little is known about how this virus interacts with oral  tissues and the local immune environment. The salivary gland may serve as a unique site of viral presence and  immunological modulation, particularly through pathways involving non-classical major histocompatibility  complex (MHC) class I molecules. This project aims to investigate fundamental aspects of the innate immune  response to SARS-CoV-2 within the salivary gland, with a focus on the molecular interactions between virus- or  host-derived peptides and components of the mucosal immune system. In particular, we will explore how antigen  presentation mechanisms may shape or reflect local immune activity in this tissue. Identifying such mechanisms  will advance our understanding of tissue-specific immune regulation and viral tropism. The proposed research  is designed to clarify basic molecular and cellular processes that underlie host-pathogen interactions in the oral  cavity. By studying immunological dynamics in the salivary gland, this work will contribute to a framework for  understanding mucosal immunity and may reveal foundational principles of immune surveillance in non-respiratory tissues.

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Centers for Disease Control and Prevention (U.S.)