# data[].attributes.title
Project II: Adaptive Immunity and AT1-AA in Mediating the PE Phenotype and Long-term Effects on Offspring

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National Heart Lung and Blood Institute (NHLBI)

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Preeclampsia (PE) affects 12% of deliveries in Mississippi and this incidence of PE increased significantly due to the COVID-19 pandemic rising to 24% in December of 2020. PE is characterized by placental ischemia, inflammation, vascular dysfunction, cognitive decline, hypertension (HTN), IUGR and developmental origins of disease in the offspring. We have shown that agonistic autoantibodies to the angiotensin II type I receptor (AT1- AA) cause placental and cerebral dysfunction contributing to HTN in pregnant rats which is attenuated by blockade of the AT1-AA with the peptide ‘n7AAc’. Moreover, we have shown that the inflammatory cytokine TNF- α stimulates the AT1-AA and causes HTN and cerebral dysfunction during pregnancy. One important unanswered question in PE research is the relative importance of immune mediators to cause HTN and cerebral dysfunction in the pregnant mom or to cause adult HTN in her offspring. Moreover, we don’t know the role of immune mediators as mechanisms of a PE phenotype in pregnant patients with a history (Hx) of COVID 19 infection. Preliminary data in support of AIM 1 are that placental CD4+ T cells cause HTN and cerebrovascular dysfunction in pregnant rats and lead to cognitive dysfunction at 4 months postpartum (PP). Our preliminary data supporting AIM 2 are that Etanercept reduces blood pressure in adoptive transfer recipients of PE T cells. Preliminary data supporting AIM 3 is that HTN, AT1-AA and TNF-α are produced in pregnant women with HTN and a history (Hx) of COVID during pregnancy and in adoptive transfer recipients of T cells from PE women with a COVID 19 Hx during pregnancy compared to recipients of T cells from normotensive women with a Hx of COVID during pregnancy. Based on our findings, we hypothesize that PE stimulated T cells, in the presence or absence of a past COVID infection during pregnancy, secrete TNF-α stimulating B cell secretion of AT1-AA, both of which cause cerebral dysfunction and HTN during pregnancy and programming of cerebral dysfunction and cognitive decline in adult male and female offspring which could be attenuated by either TNF-α or AT1-AA blockade. Specific Aim 1. Does perinatal administration of CD4+T cells from PE women cause HTN and cerebrovascular dysfunction during pregnancy or PP in recipient dams or lead to HTN or cognitive decline in IUGR offspring? Specific Aim 2. Does blockade of AT1-AA or TNF-α in response to perinatal administration of PE CD4+T cells improve HTN and cerebrovascular dysfunction during pregnancy or PP in recipient dams and HTN and cognitive decline in IUGR offspring? Specific Aim 3. Do CD4+T cell mediated inflammatory responses from prior COVID-19 infection lead to PE-like HTN and neurovascular dysfunction in pregnant rats and PP that could be improved with blockade of TNF-α or AT1-AA? Does blockade of AT1-AA or TNF-α in response to perinatal administration of PE CD4+T cells improve HTN and cerebrovascular dysfunction in IUGR offspring?

# data[].attributes.title
User-Centric Development of a Detection Module for a Closed-Loop Solution to Opioid Overdose

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This Phase I SBIR proposal aims to advance the commercialization of Rescue Biomedical LLC’s Automatic Antidote Delivery Device (A2D2) by first developing and commercializing its overdose detection component, the Automatic Detection Device (AD2). Despite growing awareness of opioid dangers, 81,083 opioid overdose deaths occurred in 2023, exacerbated by COVID-19. Fentanyl overdose deaths nearly doubled from 11.4 per 100,000 people in 2019 to 21.8 per 100,000 in 2021. These potent drugs can cause respiratory failure within minutes, leaving little time to administer antidotes like naloxone. This crisis has imposed immense financial burdens on the healthcare system and devastated thousands of families each year. The A2D2 is a comprehensive, closed-loop solution that combines a user-centric wearable with an implantable drug delivery system, automatically administering naloxone upon detecting opioid-induced respiratory depression. This device has the potential to (1) reduce the need for intensive treatment, (2) decrease hospitalization days, and (3) alleviate the financial burden on patients. These benefits extend to the healthcare industry by freeing up resources to address other health issues. Early customer discovery and regulatory interactions have led to the strategic decision to commercialize the detection component (AD2) separately and first. This approach provides customers with options and allows us to establish a market presence earlier, paving the way for the full A2D2 solution. Our initial focus will be on refining the detection software, strategizing go-to-market plan, and ensuring manufacturability. To achieve this, we propose the following Specific Aims for Phase I: Aim 1: Demonstrate User Acceptability: Understand patients’ willingness to wear the AD2 and validate the interface during the detection of an overdose. Aim 2. Assess Market Integration: Conduct targeted research to evaluate the market readiness and logistical considerations, including potential partnerships with clinics and marketing strategies. Aim 3. Determine Manufacturing Feasibility: Evaluate manufacturability while concurrently designing an early alpha prototype in a wearable form factor. In this Phase I SBIR proposal, Rescue Biomedical aims to validate the acceptability of an overdose detection device among OUD patients, ensuring it contacts emergency services for prompt medical intervention and has a sufficient alert notification interface. We will collaborate with RMS to quantify user willingness to adopt such devices. Additionally, we will identify stakeholders at private treatment centers, such as LCDCs and psychiatrists, to assess their openness to incorporating new solutions like the AD2. Finally, with the help of Kablooe Design, we will ensure the AD2 can be manufactured on a large scale, allowing us to refine the design early during development. The long-term objective of this project is to reduce opioid overdose-related deaths by providing a reliable, user-friendly device that can be integrated into the daily lives of high-risk patients. By addressing the urgent need for effective overdose detection and immediate prompt for medical intervention, this project aligns with the mission of the funding agency to improve public health and save lives. The research design includes a comprehensive approach to user adoption, market integration assessment, and manufacturability evaluation, ensuring the project's relevance and feasibility for broad-scale implementation.

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Small Business Innovation Research Grant

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Impact of Spatial and Social Determinants on Invasive Fungal Infection Risk

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National Institute of Allergy and Infectious Diseases (NIAID)

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: Invasive fungal infections (IFIs) are a growing public health challenge, leading to over 1.5 million deaths each year worldwide. Contextual factors are believed to be critical components of IFI risk as evidenced by historical fungal outbreaks associated with specific geographic distributions and ecological disruptions. Certain communities are thought to be particularly vulnerable with greater exposure to high-risk contextual factors, leading to higher rates of and worse outcomes from IFIs. In addition, socioeconomic status may impact IFI outcomes, due to delays in diagnosis, access to care, and quality of care. However, prior studies of IFI epidemiology have focused primarily on host factors without adequately considering the uneven distribution of hazards and their spatiotemporal trends related to socioeconomic factors. The objective of this proposal is to assess the impact of social determinants on IFI risk by leveraging a national data source, the National COVID Cohort Collaborative, and a more granular hospital system electronic-health medical records data source. In Aim 1, we will determine neighborhood-level contextual and socioeconomic predictors of IFIs. In Aim 2, we will examine the association between individual socioeconomic status factors and clinical outcomes of IFIs. This work will advance our understanding of the spatial and social determinants of IFI risk and outcomes as well as provide a robust training platform for the award recipient, Dr. Lucy Li. Through both research and career development training, Dr. Li will acquire essential skills in large data analysis, including advanced methods in spatial science and social factors research, time series analyses, and risk prediction modeling. Dr. Li will then be well positioned to be an independent clinical investigator focused on IFIs in at-risk populations with an expertise in integrating spatial and social factors data into population health analyses.

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International Classification of Disease Codes

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Impact of SARS-CoV-2 on the cerebrovasculature as a risk factor for VCID: Role of Wnt/beta-catenin

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COVID-19 increases the risk of vascular contributions to cognitive impairment and dementia (VCID). VCID is one of the most prevalent forms of dementia, so the potential public health impact of the COVID-19 pandemic on future VCID is substantial. However, the mechanisms by which COVID-19 modifies VCID are unknown. Identifying mechanisms that regulate how prior COVID-19 influences the brain endothelial cell response to vascular stress is important. Here, we provide preliminary evidence that COVID-19 decreases resistance to VCID by weakening the blood-brain barrier (BBB). This is accompanied by cerebrovascular inflammation. This grant will test the novel mechanism that SARS-CoV-2 infection accelerates VCID by suppressing cerebrovascular Wnt/β-catenin signaling. In Aim 1, we determine how prior SARS-CoV-2 infection influences BBB permeability and cognition upon subsequent vascular insult, by genetic and epigenetic modification. In Aim 2 we use endothelial-targeted genetic interventions to assess the contribution of Wnt/β- cat targets to resistance to post-infectious VCID. In Aim 3, we ask whether established post-infectious VCID can be reversed by increasing cerebrovascular Wnt/β-catenin. These studies could lead to novel approaches to identify individuals at high risk for VCID and novel potential therapeutic strategies to mitigate the impact of prior infection on the development of dementia.

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vascular cognitive impairment and dementia

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Development of a stable mRNA prophylactic vaccine against SARS-CoV-2 omicron variant

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National Institute of Allergy and Infectious Diseases (NIAID)

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Infectious disease remains one of the leading causes of illness and mortality worldwide. The recent coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) led to widespread illness and death, disrupting public health and economy. It has been successfully mitigated thanks to the development and global application of the novel messenger RNA (mRNA) vaccine technology. While mRNA vaccines have offered significant protection, the high mutation rate of SARS-CoV-2 necessitates ongoing development of updated vaccines to combat new variants. While mRNA vaccines have shown remarkable effectiveness against COVID-19 by stimulating both humoral and cellular immune responses, the main limitation lies in the inherent instability of mRNAs at normal conditions without protection. Therefore, current mRNA and mRNA formulations require ultralow temperatures for storage and transportation. Recognizing the instability challenge, we proposed to develop a novel “RNA-plex” technology, which uses an “carrier-base” polymer to bind to mRNA molecules, preventing them from degradation in fridge or room temperature during storage. It significantly reduces the transportation and distribution costs, and makes mRNA vaccines more accessible globally, especially in areas with limited cold chain facilities. Notably, this mRNA protection technology can universally shield various mRNAs, is compatible with multiple delivery systems, and significantly enhances mRNA translation in cells, suggesting its promising potential for diverse therapeutic and research applications. In this proposal, we will apply this mRNA stabilization technology named “RNA-plex” in the development of stable and efficient vaccines for SARS-CoV-2 prevention. Specifically, we will optimize the composition and formulation of RNA-plex to maximize its protective efficacy for SARS-CoV-2 omicron variant spike protein mRNA. Next, we will apply it in preparing prophylactic lipid nanoparticle (LNP) mRNA vaccines with high stability, enhanced antigen translation efficiency, and superior vaccination effectiveness compared to conventional approaches against emerging viral threats, using the recent SARS-CoV-2 omicron variant XBB.1.5 as a proof-of-principle model. Specific Aims: Aim 1. Stabilization of SARS-CoV-2 omicron variant mRNA using RNA-plex technology and develop an LNP mRNA vaccine. Aim 2. Evaluate the efficacy of LNP-RNA-plex vaccine in eliciting immune responses and protection against SARS-CoV-2 Omicron variant.

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Effects of a natural experiment on maternal and infant health

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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

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HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES

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Rates of adverse maternal and infant health outcomes (e.g., preterm delivery, severe maternal morbidity, and mortality) in the United States (US) substantially outpace other high-income nations and are unacceptably high among women identifying as Black, American Indian, or Alaska Native and those living in rural areas. Municipalities and states across the US have begun implementing cash transfer programs, many targeted to pregnant women or families, with the objective of improving maternal and infant health through poverty reduction. Yet, evidence about the impact of cash transfers (i.e., intentional monetary transfers to individuals or households) on maternal and infant health in the US is decidedly mixed. A temporary expansion of the US Child Tax Credit (CTC) that led to an unprecedented 35% reduction in child poverty in 2021 offers an ideal natural experiment with which to test the impact of receiving monthly cash transfers during pregnancy on maternal and infant health. Surprisingly, our own preliminary ecological study indicated that the 2021 CTC expansion preceded an unexpected increase in low birth weight (LBW) among births to women likely to have received the CTC.17 This work calls into question the straightforward assumption that cash transfers in the US (such as the CTC) would improve infant health. The overall goal of this proposal is to thus examine the impact of cash transfers during pregnancy on maternal and infant health and health disparities in the US. The specific aims of this proposal are to 1) Estimate impacts of receiving CTC monthly payments during pregnancy on maternal and infant health, and 2) Determine whether impacts of receiving CTC monthly payments during pregnancy on maternal and infant health differ by race/ethnicity, socioeconomic status, or rurality. Exploiting, as a natural experiment, the unexpected and temporary monthly CTC payments received by ~40% of pregnant women between July and December of 2021, we will construct a simulated instrument to estimate individual-level impacts of the CTC expansion during pregnancy on maternal and infant health, and we will use rigorous methods to account for other health, social, policy, and economic changes during the COVID-19 pandemic. We will use two high-quality survey and administrative datasets (i.e., US Natality data and the Pregnancy Risk Assessment Monitoring System survey) to assess maternal and infant health measures plausibly impacted by cash transfers. Our study team, with 15 years of collaboration and expertise in maternal health, impacts of cash transfers on health, and the proposed methods and datasets, is ideally poised to achieve our goal. Our proposal responds directly to an NICHD Notice of Special Interest. Achieving these aims will increase understanding of how cash transfers impact maternal and infant health and will inform development of ongoing programs and policies, including local cash transfer pilot projects and future changes to the CTC and other tax credits.

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National Institute of Child Health and Human Development

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Platelet Regulation of Monocyte Responses in Vascular Inflammation

# data[].attributes.funder_divisions[]
National Heart Lung and Blood Institute (NHLBI)

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Trained immunity is a biologic process in which prior immune stimuli durably ‘trains’ innate immune cell responses to future stimulation. Trained immunity is driven by changes in glycolysis and its metabolites, leading to histone modifications, DNA methylation, or changes in non-coding RNA (ncRNA) that immune programs subsequent monocyte/macrophage responses to either be greater or lessened. Trained immunity research has largely focused on how pathogen derived molecules immune train monocytes and macrophages (mono/macs), but there are also indications of cell based trained immunity. We recently made the novel discovery that resting platelet interactions with mono/macs via platelet CD47 increased glycolysis and durably programmed mono/macs through changes in histone methylation to limit TLR responses. This was the first demonstration of endogenous cell mediated innate immune training. We now propose the novel idea that in healthy conditions, resting platelet-monocyte interactions limits monocyte TLR responses, that are overcome by platelet activation. Because platelets are small, they circulate at the interface between endothelial cells and leukocytes, ideally positioning platelets as sensors of both vascular health and tissue injury/infection. How activated platelets induce and amplify immune responses has received an increasing amount of attention, including significant work from our group. However, studies have also shown that normal platelet counts maintain immune homeostasis and our recent manuscript provides a mechanistic framework for how resting platelets immune train monocytes to a tolerant phenotype. We found that circulating monocytes from thrombocytopenic (low platelet count) mice produced more inflammatory cytokines in response to TLR ligands. Resting platelets express CD47 that interacts with circulating monocytes to induce glycolysis dependent changes in histone methylation, epigenetically modifying mono/macs to a more immune tolerant phenotype. Thrombocytopenia (clinically defined as a platelet count less than 150,000/µL) independently associates with dysregulated monocyte responses, increased plasma cytokines, prolonged morbidity, and increased mortality. A decline in platelets may also independently lead to long-term changes in mono/mac responses, for example, some COVID-19 patients have persistent/recurrent thrombocytopenia beyond the infection, and with it, prolonged inflammation. However, little is known about the mechanisms and the long-term implications of thrombocytopenia on immune responses. Hypothesis: Resting platelet-monocyte interactions immune trains monocytes to a quiescent phenotype. Aim #1. To determine the platelet-mediated signaling that leads to monocyte immune programming. Aim #2. To determine the functional outcomes of resting platelet-mediated monocyte immune programming. Aim #3. To determine the functional consequence of a loss of platelet-monocyte interactions in disease contexts.

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Scalable and Epidemiologically Interpretable Phylodynamics to Recover Heterogeneous Transmission Dynamics

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National Institute of General Medical Sciences (NIGMS)

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As pathogens are transmitted between individuals, they accumulate mutations, leaving a footprint of the transmission history in the pathogen genomes. Using phylogenetic methods, we can reconstruct the transmission history connecting individual cases from these genomes, by reconstructing the relationships of the pathogens. We can then infer population-level transmission dynamics, from the ancestral relationships of the pathogens, or phylogenies, using phylodynamic methods. Infectious disease transmission and disease burden are highly heterogeneous, differing between neighborhoods, across age, and socioeconomic groups, and racial and ethnic lines. This heterogeneity means that it is crucial to a) be able to illuminate differential disease burdens and b) account for these heterogeneities when modeling or forecasting infectious disease outbreaks. Traditional approaches based on reported caseloads are often insufficient for capturing the full scope of highly heterogeneous transmission dynamics. Phylodynamics offers a potential solution, as it infers transmission dynamics from the connectivity of cases, providing an opportunity to disentangle these complex patterns. However, limitations in our available toolbox prevent us from fully utilizing the vast availability of pathogen genomes to study these complex transmission dynamics, as current phylodynamic approaches suffer from multiple challenges. With the advent of widely available sequencing, phylodynamic tools are not computationally efficient enough to analyze the amounts of data generated at the granular scales crucial to understanding transmission dynamics. Additionally, the model parameters need to be epidemiologically interpretable to be actionable. In this project, we seek to address these two points by developing novel approaches to reconstruct transmission dynamics from pathogen sequence data. We will develop novel phylodynamic tools to reconstruct transmission dynamics at a granular scale by integrating neural networks into phylodynamic likelihood calculations that we show in preliminary results to dramatically improve computational efficiency and scalability. Phylodynamic methods are parameterized by more or less abstract parameters that either have no direct epidemiological meaning or are contingent on idealized assumptions about disease spread. We will establish how and when current approaches return biased results when reconstructing city-scale transmission dynamics, describe how they can be used to estimate actual disease burden, and test them using SARS-CoV-2 sequence data collected by Kaiser Permanente Southern California (KPSC) and in the UK over the pandemic. Finally, we will develop ways to quantify the factors influencing disease burden, such as geography, age, and socioeconomics. We will apply these tools to KPSC SARS-CoV-2 data, where we can access rich patient metadata to study these patterns. Our overarching goal is to utilize phylodynamic inference of heterogeneous transmission dynamics to parameterize complex infectious disease dynamic models and improve prediction accuracy.

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COPD GENE - GENETIC EPIDEMIOLOGY OF COPD - TASK AREA A: YEAR 3 - AUGUST 10, 2025 - AUGUST 9, 2026

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National Heart Lung and Blood Institute (NHLBI)

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Genetic Epidemiology of COPD (COPDGene) is a multi-site longitudinal cohort study of current and former smokers to better understand risk factors, natural history, and genetic contributions of chronic obstructive pulmonary disease (COPD) as well as other smoking-related diseases. The purpose of this acquisition is to fund a 15-year follow-up in-person clinical visit (Visit 4) of this cohort, to be re-enrolled from approximately 19 active Clinical Study Centers. A Visit 4 of COPDGene subjects is needed to identify clinical, physiological, imaging, and Omics determinants of COPD and other disease progression in elderly subjects, to assess the impact of COVID-19 on COPD and other disease progression, and to discover determinants of severe COPD development in subjects with preserved ratio, impaired spirometry (PRISm). The acquisition will also support the maintenance of previously collected data and biospecimens, regulatory oversight of the study, and analysis of study data and study biospecimens. The goal of COPDGene is to use extensive longitudinal imaging, physiology, and Omics molecular data in combination with genetics in the COPDGene cohort to identify high-risk subgroups with distinct diagnostic, prognostic, and therapeutic implications. COPDGene has been funded for 15 years through grants and cooperative agreements awarded by NHLBI to National Jewish Health and Brigham and Women’s Hospital. Grant applications for the three Phases of COPDGene [Phase 1: baseline visit (“Visit 1”); Phase 2: five year follow-up (“Visit 2”); Phase 3: ten year follow-up (“Visit 3”)] were all submitted to the parent NIH R01 Funding Opportunity Announcement. Study investigators originally recruited 10,198 current or former smokers in Phase 1. Including nonsmoking controls from both Phase 1 and Phase 2, COPDGene has recruited a total 10,718 subjects all of whom have been extensively phenotyped clinically and radiologically. Additional data collected on these participants include whole genome sequencing as well as RNA sequencing, proteomics, metabolomics, and DNA methylation data from collected blood samples. Investigators have published more than 450 publications, the vast majority of which were peer-reviewed, using COPDGene data. COPDGene also serves as a parent study for many ancillary studies, using public or private funding, a subset of which have collected additional data on all or a subset of participants. COPDGene is overseen by an NHLBI-convened Observational Study Monitoring Board (OSMB). The Visit 4 (15-year follow-up) evaluations will include, where possible, lung function tests (spirometry), questionnaires (including COVID-19 assessment), chest computerized tomography (CT), other functional assessments (e.g., six minute walk distance), and collection and storage of biospecimens from 3,500 of the original 10,718 COPDGene subjects. In addition, this acquisition will support continuation of semi-annual long-term follow-up of the COPDGene cohort and other contact with the cohort as needed, oversight of clinical sites and human subjects protection, maintenance of the database and biobank, continued coordination with NIH and NHLBI data resources, activities relevant to the data management and sharing plan, analysis of data, travel to meetings, and publication costs.

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National Heart  Lung  and Blood Institute

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United States National Institutes of Health

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Optimal Ventilator Management in Patients with ARDS on ECMO

# data[].attributes.funder_divisions[]
National Heart Lung and Blood Institute (NHLBI)

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Research Plan: Acute respiratory distress syndrome (ARDS) is a severe and common condition that affects 10% of patients in the intensive care unit (ICU), and was a major cause of morbidity and mortality during the COVID-19 pandemic. While mechanical ventilation is often necessary for ARDS, it can also induce additional lung injury known as ventilator induced lung injury (VILI). VILI may be minimized by using low tidal volumes/driving pressure and with positive end expiratory pressure (PEEP). Some patients with severe and refractory ARDS require veno-venous extracorporeal membrane oxygenation (V-V ECMO), the highest level of life support which provides oxygen and removes carbon dioxide from the blood using an external device. A major benefit of ECMO is thought to be the ability to minimize VILI; however, the optimal ventilator settings for patients with ARDS on ECMO are not known. Current guidelines use a one-size-fits-all approach. Our central hypothesis is that personalized PEEP adjusted by measuring intrathoracic pressures via esophageal manometry (Pes) will decease VILI as assessed by biomarkers of inflammation (main outcomes IL-6 and sRAGE). To carry out these aims, we plan to prospectively randomize 62 patients with ARDS on V-V ECMO and neuromuscular blockade and perform serial biomarker measurements with PEEP of 10 cmH2O (ECMO guidelines) vs. PEEP guided by esophageal manometry. In addition to biomarkers of VILI, we will assess differences in other physiological outcomes including pulmonary mechanics and gas exchange. Although this proposal focuses on patients on ECMO, we believe the knowledge gained will have relevance for all patients with ARDS. Career Development Plan: The goal of the PI, Dr. Mazen Odish, is to personalize ARDS and ventilator strategies for those on ECMO based on physiology and biomarkers. The PI has an interest in applied physiology and critical care, this award will help him refine these skills and develop new skills in clinical trials, statistics, and patient-oriented research, to test rigorously methods to care for critically ill patients with ARDS with or without ECMO. To obtain these new skills Dr. Odish and his excellent and multi-disciplinary mentoring/advisory team (led by Drs. Owens and Malhotra, plus outstanding statistical and methodologic support) has three main training goals. 1) Pulmonary mechanics and biomarkers during ARDS, 2) control of breathing and measurement of work of breathing during ARDS/mechanical ventilation, and 3) clinical trial design and statistical training. These training activities are tailored for the PI to achieve his goals and maximize career development towards becoming an independent physician scientist. Furthermore, his structured course work will lead to a Masters of Advanced Studies in Clinical Research. Dr. Odish is at the right place and time in his career to align his clinical expertise in ECMO and ARDS with his research goals to understand optimal ventilator settings and therapies. Eventually his work and new skill set may improve the lives of all people suffering from respiratory illness.