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NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Progressive supranuclear palsy (PSP) is a rare neurodegenerative motor disorder affecting approximately 20,000 people in the U.S. Clinical hallmarks of PSP are early loss of balance and falls, together with impairment in saccadic eye movements. Additional features often mimic Parkinson’s disease (PD), but PD treatments provide little to no therapeutic benefits in PSP. Histopathologically, PSP is characterized by the presence of insoluble aggregates of the microtubule-associated protein, Tau. While disease-causing mutations to the Tau- encoding MAPT gene have been described, the majority of PSP cases are idiopathic. Postmortem analysis of PSP patient brains show Tau pathology in several motor control regions, such as the basal ganglia (e.g. striatum, subthalamic nucleus, substantia nigra) and midbrain eye movement nuclei. Recent findings indicate basal ganglia output nuclei, such as the substantia nigra, are among the first sites of neuronal pathology. Tau pathology in these regions may lead to physiological dysfunction of motor circuits, in turn driving motor symptoms seen in PSP. To test this hypothesis, we recently repurposed a previously described Tau transgenic mouse and determined that Tau pathology in the mice was sufficient to mimic two key clinical aspects of PSP: gait and eye movement abnormalities. Using custom-built gait and eye movement recording systems, we observed that Tau hP301S mice had impaired coordination and vertical eye movements. Furthermore, we find these phenotypes correlate with pathology in many PSP-associated motor control regions, such as the substantia nigra and mesencephalic locomotor region. We also find that expressing mutant Tau specifically in the substantia nigra is sufficient to mimic these same abnormal phenotypes. In this proposal, I will use these two new mouse models to test my central hypothesis that Tau pathology leads to behavioral deficits via physiological abnormalities in midbrain motor regions, the substantia nigra pars reticulata and the mesencephalic locomotor region. I will use a combination of in vivo electrophysiology, ex vivo patch-clamp recordings, and quantitative measures of eye movement and gait to identify these links between pathology, physiology, and behavior. Understanding these mechanisms may help focus future work on both the underlying mechanism of PSP and identify new treatment strategies. The experiments proposed in this study expands upon my prior ex vivo slice electrophysiology training and adds training in in vivo electrophysiology and complex behaviors. In addition, I have assembled an expert mentoring team to provide guidance in my career development with the goal of launching a career as a successful independent investigator at a biomedical research institution.

NIAID - National Institute of Allergy and Infectious Diseases

In the United States and globally, respiratory syncytial virus (RSV) is a leading cause of morbidity and mortality in infants under 6 months, leading to ~50,000 deaths per year. Preterm infants are at particularly high risk of severe disease. To boost protection, a bivalent RSV vaccine formulated as recombinant pre-Fusion glycoprotein (preF) was recently licensed for use in pregnancy and provides ~70% protection from severe RSV disease in infants under 6 months of age. To date, the efficacy of this vaccine has been attributed solely to the transplacental transfer of maternal IgG to the fetus. However, maternal vaccination may also impact breastmilk immunity, where breastmilk exposure and breastmilk RSV-specific IgG are both associated with protection from RSV infection and reduced disease severity. We and others have also demonstrated that breastmilk also contains RSV-specific IgA and mucosal memory T cells, which increase during RSV-infection in the maternal-infant dyad. Breastmilk IgG and IgA may be systemically absorbed in the first few days of life and could contribute to viral neutralization. In addition, animal data demonstrate that breastmilk T cells can integrate into offspring organs including the lung, where they may facilitate viral clearance. Together, these observations suggest that adaptive immunity derived from breastmilk is functionally distinct from transplacental IgG and, importantly, can provide mucosally active IgA, IgG, and durable T cell protection to the infant. However, the impact of RSV-VX on breastmilk immunity is currently unknown. To address this knowledge gap, we have recently demonstrated that there is increased preF- specific IgA and IgG in the breastmilk of women who received RSV-VX compared to those who did not. Thus, our central premise is that breastmilk provides a distinct form of mucosal immunity to the infant which can be boosted with vaccination. Further, prior data demonstrate that transplacental transfer of IgG is reduced in preterm dyads, but early breastmilk IgA and T cell concentrations are increased. Thus, we hypothesize that the relative importance of RSV-VX on breastmilk immunity is greater in preterm versus term infants, where preterm infants receive less transplacental IgG but more breastmilk IgA and cellular immunity. To test our hypothesis, we will enroll a cohort of pregnant women at delivery who did or did not receive RSV-VX, including preterm and term deliveries. We will collect maternal and cord blood at delivery, maternal breastmilk and blood at 2-, 6-, and 12- weeks postpartum, and infant blood at 12-weeks. In Aim 1, we will determine the impact of RSV-VX and preterm delivery on breastmilk and peripheral RSV-specific antibody levels and function. In Aim 2, we will determine the impact of RSV-VX and preterm delivery on frequency and function of peripheral blood and breastmilk RSV- specific CD4 and CD8 T cells. The proposed studies will address a critical knowledge gap regarding the ability of RSV-VX to boost mucosal breastmilk and peripheral immune responses in term and preterm dyads. These data will provide rationale for the development of next generation maternal vaccines designed to induce mucosal immunity as a targeted strategy to improve infant protection.

NIAID - National Institute of Allergy and Infectious Diseases

Accidental or deliberate radiation exposure of humans remains a major health concern, due to the paucity of medical countermeasures (MCMs) to ameliorate radiation-induced damage. While high dose radiation exposure is generally fatal, even low dose whole body (WBI) or partial radiation exposure can have acute- and/or delayed- negative impacts that appear to act through disruption of the immune system. The cytoreductive effects of WBI have long been exploited in conjunction with chemotherapy as a preparative regimen prior to hematopoietic stem cell transplant in patients with blood cancer to deplete malignant cells and suppress the immune system. While there is strong evidence that radiation kills rapidly dividing cells, a hallmark of the immune system, and induces inflammation that can mediate tissue destruction, the precise nature of radiation induced immune-dysfunction is not well understood. This knowledge gap is a key impediment to development of MCMs to treat radiation exposure. For one example, memory CD8 T cells provide enhanced resistance to re-infection and malignancies. However, most studies in the literature examine the impact of radiation exposure on the capacity of the host’s naïve CD8 T cells to mount a new (primary) immune response and just a few reports have looked at how radiation exposure influences the longevity and protective capacity of pre-existing pathogen or vaccine-induced CD8 T cell memory. Memory CD8 T cell populations have the job of surveying the entire body for signs of re-infection. They accomplish this task using two complimentary and interactive strategies. This first strategy involves populations of memory CD8 T cells that survey the body by using the circulatory system (circulating memory CD8 T cells - Tcircm). The second strategy involves the generation of a population of non-circulating memory CD8 T cells (called T resident memory, Trm), generally in the tissue of pathogen entry. These cells, which persist long-term in tissues, provide rapid detection of re-invading pathogens and then send out mediators to recruit other cells of the immune system to the site of infection. Importantly, our recent data obtained after WBI or partial (targeted) thorax radiation suggest that sublethal ionizing radiation inflicted numerical and functional damage to Tcircm and Trm cells that diminished their ability to provide protection to pathogen-re-encounter. Our long-term goal is to precisely identify mechanisms that govern maintenance, differentiation and function of infection and/or vaccine- induced memory CD8 T cell subsets and explore modalities to recover memory CD8 T cell responses in radiation survivors. We will address our long-term goal through the following specific aims: SA1 - Delineate the tissue-specific impact of WBI on pathogen-specific Trm and evaluate targeted vaccine strategies to restore memory CD8 T cell numbers and function after irradiation. SA 2 - Define mechanisms underlying WBI-induced numerical and functional diminishment of Tcircm and exhausted (Tex) CD8 T cells generated after acute or chronic viral infections.

Imperial Oil

Supports STEM education, Indigenous community development, and environmental programs across Canada.

Watervliet

Implementation of ERP and Financial System

Substance Abuse and Mental Health Services Adminis

Implementing Zero Suicide in Health Systems

Star, Inc., Lighting the Way…

Improvement - Sprinkler System

Meadowbrook Community Gardens and Orchards

Meadowbrook Community Gardens and Orchards, (MCGO), will improve our irrigation system, (currently irrigation is all done by hand by volunteers), replace old and worn tools, repair raised beds and add a few more, and buy bulk soil amendments and compost to improve soil quality. All of the ese improvements will allow us to better achieve our purpose of producing more food to meet the growing needs of our community.

NIA - National Institute on Aging

PROJECT SUMMARY Up to 3.1% of women in the United States experience premature menopause (menopause before age 40) and another 6.2% experience early menopause (menopause between age 40-45) due to a spectrum of surgical and non-surgical conditions. Premature/early menopause results in estrogen deprivation which has significant health consequences and adversely affects quality of life. Compared to natural menopause, women who undergo premature/early menopause have an increased risk for cardiovascular disease, osteoporosis, and neurological/psychological conditions, leading to a higher mortality risk. Systemic hormone therapy (HT) is highly effective in mitigating the short- and long-term consequences of estrogen deprivation and is recommended by guidelines from national and international professional organizations. However, research on HT use in women with premature/early menopause is sparse and the limited data available suggest severe underuse. Because women at younger ages are less prepared of menopausal transition and may face greater challenges in work, life, and health care, there is a critical need for research on premature/early menopause. The overarching goal of this project is to improve the long-term health of women with premature/early menopause by understanding factors influencing their HT use and developing a preliminary tool for identifying women at high risk for underuse. We will focus on women without malignancy or hereditary predisposition for cancer – a homogeneous population to better isolate influencing factors. Within this population, we propose the following specific aims: 1) to characterize the overall trajectory and heterogeneity in HT use and identify patient and physician factors associated with HT initiation and continuation; 2) to ascertain patients' and physicians' perceived barriers and facilitators to HT use; and 3) to develop a dynamic risk prediction model for HT underuse and explore the feasibility of a patient prioritization tool for HT counseling. We will achieve these aims by analyzing a unique dataset that integrates insurance claims data with electronic health record data and applying novel analytical approaches to characterize patients’ longitudinal trajectory of HT use (both the overall pattern and heterogeneity among patients), examine physician peer influence in HT practice, and develop artificial intelligence/machine learning-based risk prediction models. This will be supplemented by primary data collection using a mixed methods approach – combining qualitative interviews and focus groups with quantitative surveys of patients and physicians – to uncover individual, structural, and system-level factors influencing HT initiation and continuation and inform proactive interventions for improving HT use. By understanding care patterns related to HT use in women with premature/early menopause, its influencing factors, and characteristics of patients at particularly high risk for HT underuse, this project addresses an important but understudied clinical question. The findings can facilitate targeted interventions and better equip us with the knowledge and tools to improve care for this large population of women.

FIC - John E. Fogarty International Center for Advanced Study in the Health Sciences

Project Summary Candidate: Roxanna Garcia, MD, MS, MPH is a neurosurgeon and fellowship trained neuro-critical intensivist serving as Assistant Professor of Neurological Surgery at Northwestern University. Dr Garcia’s long-term career goal is to be an independent physician-scientist who uses expertise in implementation research to improve adoption of evidence-based practice in neurosurgical disease, with a focus on traumatic brain injury (TBI) globally. Background: TBI is a public health crisis that disproportionately affects low- and-middle income countries (LMICs), where the risk of mortality is 3 to 4-fold greater than compared to high-income countries. The incidence of TBI represents the leading cause of neurologic disease globally, with approximately 69 million incident cases every year. Moderate TBI (Glasgow Coma Scale[GCS] scores 9-12) and severe TBI (GCS scores 3-8, msTBI) can produce lifelong disability, and is estimated to contribute to over 30% of deaths caused by trauma. Timing to surgery is an important factor, especially among patients with structural lesions. A four- hour timeframe from event to surgical decompression can improve survival. Health system factors delaying timing to intervention have not evaluated, especially in LMICs. Training Plan: In order to achieve research independence, Dr Garcia will need to strengthen skills in (1) applying implementation science methodologies, (2) learning mixed methods to develop (3) expertise in clinical trials research design. Dr Garcia will be mentored by an outstanding multinational team including primary mentor Dr Andrew Naidech (Northwestern University), and Dr Patricia Garcia (Universidad Peruano Cayetano Heredia). Her co-mentors Dr Lisa Hirschhorn (Northwestern University) and Dr Fizan Abdullah (Northwestern University). This team represents experts in health systems and services research, as well implementation science and global health and surgical research. Research Plan: With guidance from her mentor team, Dr Garcia will apply the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to understand to open cranial surgical intervention for msTBI in the acute emergency setting among health providers in Lima, Peru at high volume trauma centers. The study will continue to build upon an existing prior NIH related post-doctoral research fellowship experience. Dr Garcia will (1) explore the current clinical practices, and define the barriers, and facilitators influencing timing to open cranial surgery for patients suffering from msTBI. She will then apply (2) mechanistic mapping through a co-creation process to create codesign strategies for addressing critical barriers and leveraging facilitators among key stakeholders; and (3) conduct a feasibility implementation pilot to improve timing of open cranial surgery for msTBI. The study will utilize mixed-methods including semi- structured interviews, surveys and focus groups to inform an implementation research logic model and plan, and inform an R01 proposal focused on implementation and sustainment.

FIC - John E. Fogarty International Center for Advanced Study in the Health Sciences

Project Summary Candidate: Roxanna Garcia, MD, MS, MPH is a neurosurgeon and fellowship trained neuro-critical intensivist serving as Assistant Professor of Neurological Surgery at Northwestern University. Dr Garcia’s long-term career goal is to be an independent physician-scientist who uses expertise in implementation research to improve adoption of evidence-based practice in neurosurgical disease, with a focus on traumatic brain injury (TBI) globally. Background: TBI is a public health crisis that disproportionately affects low- and-middle income countries (LMICs), where the risk of mortality is 3 to 4-fold greater than compared to high-income countries. The incidence of TBI represents the leading cause of neurologic disease globally, with approximately 69 million incident cases every year. Moderate TBI (Glasgow Coma Scale[GCS] scores 9-12) and severe TBI (GCS scores 3-8, msTBI) can produce lifelong disability, and is estimated to contribute to over 30% of deaths caused by trauma. Timing to surgery is an important factor, especially among patients with structural lesions. A four- hour timeframe from event to surgical decompression can improve survival. Health system factors delaying timing to intervention have not evaluated, especially in LMICs. Training Plan: In order to achieve research independence, Dr Garcia will need to strengthen skills in (1) applying implementation science methodologies, (2) learning mixed methods to develop (3) expertise in clinical trials research design. Dr Garcia will be mentored by an outstanding multinational team including primary mentor Dr Andrew Naidech (Northwestern University), and Dr Patricia Garcia (Universidad Peruano Cayetano Heredia). Her co-mentors Dr Lisa Hirschhorn (Northwestern University) and Dr Fizan Abdullah (Northwestern University). This team represents experts in health systems and services research, as well implementation science and global health and surgical research. Research Plan: With guidance from her mentor team, Dr Garcia will apply the Exploration, Preparation, Implementation, and Sustainment (EPIS) framework to understand to open cranial surgical intervention for msTBI in the acute emergency setting among health providers in Lima, Peru at high volume trauma centers. The study will continue to build upon an existing prior NIH related post-doctoral research fellowship experience. Dr Garcia will (1) explore the current clinical practices, and define the barriers, and facilitators influencing timing to open cranial surgery for patients suffering from msTBI. She will then apply (2) mechanistic mapping through a co-creation process to create codesign strategies for addressing critical barriers and leveraging facilitators among key stakeholders; and (3) conduct a feasibility implementation pilot to improve timing of open cranial surgery for msTBI. The study will utilize mixed-methods including semi- structured interviews, surveys and focus groups to inform an implementation research logic model and plan, and inform an R01 proposal focused on implementation and sustainment.

U.S. National Science Foundation

Improving Undergraduate STEM Education: Directorate for STEM Education

NIGMS - National Institute of General Medical Sciences

Abstract: Cell signaling regulates information transfer across tissues through graded ligands that interact with receptors. Across evolution, ligand and receptor proteins co-evolve, with changes in one protein being counterbalanced by changes in its partner, thus preserving successful interactions that promote development rather than pathology. Despite the importance of co-evolution in speciation and disease, our understanding of these reciprocal processes primarily relies on bioinformatics predictive tools and in vitro systems like yeast two-hybrid assays. Currently, there is no robust in vivo system, at moderate cost, to validate the co-evolution of multiple cell-signaling components. Given the differences in physiological conditions across tissues that impact protein interactions, we will develop in vivo genetic and molecular platforms for investigating co-evolving proteins. Research using Drosophila melanogaster has greatly contributed to both basic and medical research at a low cost. Building on our extensive experience with Drosophila species, we plan to generate two new in vivo systems to study the co- evolution of Gurken (GRK), a TGF-alpha ligand that activates the epidermal growth factor receptor (EGFR), endogenously. Drosophila oogenesis is a powerful model system for studying EGFR-guided axis formation and eggshell morphology, providing simple phenotypic readouts. Although the pathway and the underlying mechanism, a localized source of GRK, are conserved among Drosophila species, we have observed dramatic variations in the ability of GRK orthologs to signal interchangeably across species, ranging from no signal to a striking overactivation of EGFR signaling. The new in vivo platforms will allow us to thoroughly explore the effects of a histidine-rich domain loss in GRK on EGFR activation across different subgenera. Additionally, we will investigate the causes of EGFR overactivation when both GRK and EGFR are substituted with their homologs. S2 culture cells will be engineered with biosensors for EGFR signaling, providing a robust system to prioritize computationally predicted co-evolving sequences in GRK and EGFR for in vivo studies. Furthermore, we will examine the evolution of EGFR signaling targets, including the Tbx-20 homologs, Midline (MID) and H15, in relation to changes in signaling intensity and duration. Finally, we will study the evolution of cis-regulatory modules (CRMs) that control the expression of Mid/H15 tandem paralogs in oogenesis and other fly tissues. Our comprehensive and multidisciplinary approach-- combining new in vivo systems, computational, biophysical, analytical, and CRISPR/Cas9 genome engineering tools-- provides an exciting new path for identifying the co- evolving domains in ligands and receptors that control signaling levels. By investigating these domains in vivo, under natural physiological conditions, we will advance our understanding of cell signaling mechanisms, which could lead to new strategies for addressing tissue pathologies. The research field will benefit from new in vivo platforms to explore co-evolving processes during development and homeostasis. The EGFR signaling field will gain high-resolution analyses of co-evolving sequences that control signaling levels and duration in vivo.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

In 2023, about 4750 Americans died while awaiting a kidney transplant (KT), but over 8,500 kidneys were recovered and not transplanted. The National Academies of Sciences, Engineering, and Medicine (NASEM) declared kidney non-utilization a critical problem that mandates immediate attention and remedy. Highly prioritized candidates receive many offers for superior kidneys, but also receive offers for many non-ideal kidneys that they refuse sequentially while the clock counts down to kidney non-use. Many candidates with low priority would benefit from receiving a non-ideal kidney quickly but rarely get these offers. Stratified kidney allocation is a proposed system under which patients would make an obligatory but modifiable choice between receiving a superior kidney after a longer wait or a non-ideal kidney sooner. Stratified kidney allocation might increase organ utilization while shortening wait times and improving transplant outcomes for selected patients. Prior work has shown that patients have misperceptions about the dimensions of kidney quality, underestimate the survival benefit of transplant with non-ideal kidneys, and alarmingly, are given a very limited role in decisions about offer quality. While stratified allocation might expedite and increase the use of non-ideal kidneys, impacts are unknown because myriad and sundry details such as which deceased donor kidneys would be categorized as non-ideal, which candidates would select which quality category, etc., have never been specified, nor have patient perceptions about acceptability been investigated. We will build expert consensus on the design of stratified kidney allocation, estimate the impact of stratified allocation to assist policymakers, and investigate attitudes and perceptions of patients, care partners, and providers on shared decision making about kidney offer acceptance, and on making a choice to receive either superior or non-ideal kidneys. Our aims are (1) To understand patient and care partner attitudes, perceptions, and preferences about stratified allocation, shared decision-making, and needs for transparency around organ offers and declines, (2) to assess transplant provider attitudes, perceptions, and preferences about a stratified allocation system, and (3) to estimate the impact of stratified allocation on kidney utilization, and to estimate waiting time for KT candidates choosing either to receive either superior or non-ideal offers. This research will take stratified allocation from a speculative proposal to a concrete policy design that supports deliberation and possible adoption, informed by the judgements of transplant experts, by patient and caregiver perceptions, and by numerical estimates of its impacts. Whether or not stratified allocation succeeds, we will, as advocated in NASEM’s 2022 report, investigate approaches for increasing transparency around offer declines, and involving patients in shared decision making about the kidney quality vs. wait time tradeoff.

Indiana Council on Developmental Disabilities

Grants from the Indiana Developmental Disabilities Council for community inclusion, self-advocacy, and systems change projects.

Indiana Department of Education

STEM education initiative grants for IN to expand science, technology, engineering, and mathematics programs in K-12 and postsecondary institutions.

Indigenous Services Canada

Funds community infrastructure on First Nations reserves including housing, water systems, schools, and community buildings.

NIAID - National Institute of Allergy and Infectious Diseases

It has long been evasive why strictly hepatotropic viruses, such as hepatitis C virus (HCV), have been associated with the generation of delayed antibody responses that are of relatively poor quality to other, more systemic infections. Studies to date investigating antiviral adaptive immune priming within the liver have been hindered by lack of a natural, biologically relevant small animal model of viral infection exclusively restricted to hepatocytes. In this proposal, we will accordingly use the HGV-related rodent hepacivirus (RHV) recently discovered by our team, which possesses several similarities to its genetic relative, including strict liver tropism, conserved replication dependence on miR-122 interaction with the viral 5' UTR, identical genomic organizational structure and polyprotein cleavage pattern, and the propensity to cause chronic infection with fibrosis and hepatocellular carcinoma tumorigenesis. Our preliminary identification of robust antibody-secreting cell (ASC) responses, both total lgG and those targeting the envelope glycoprotein E2, almost exclusively arising within the liver during both human HCV and murine RHV infection, served as the rational impetus for further investigation of how, when, and where such responses are generated. The secondary lymphoid organ (SLO) dormancy accompanying such strong ASC responses within the liver alongside their durable maintenance therein by putative cognate anchoring pairs, many of which are also critical for tethering of long-lived plasma cells (LLPCs) to stromal niches in bone marrow, collectively suggest that the liver may serve as a site conducive to both the local generation and perpetual maintenance thereafter of LLPCs during strictly hepatotropic viral infection. As our recently published findings demonstrate that viral-specific lgG is critical for viral resolution, the development of chronic infection and HCC tumors in its absence suggests that generation of plausibly locally generated humoral responses within the liver at sites of virus-induced tertiary lymphoid structures, hereafter denoted as inducible Hepatic-Associated Lymphoid Tissue (iHALT), likely serve an important functional role. The survival of LLPCs residing in the liver 1.5 years post-clearance in these mice represents a unique scenario in which the liver may also provide a suitable niche for these cells, contrary to the canonical paradigm in which the bone marrow or select SLO circumstances are exclusively capable of fostering such an environment. We propose to mechanistically determine the signaling prerequisites responsible for driving this local, successful antiviral antibody response within the liver (Aim 1) as well as the cues instructing putatively locally derived progenies to be retained directly adjacent to their generative origins (Aim 2). Understanding these processes would significantly enhance our understanding of the relationship between hepatotropic viruses capable of suppressing SLOs in a state of functional dormancy with humoral responses plausibly being housed ectopically at extra lymphoid sites. Further, these studies would likely yield important insights capable of influencing the current paradigm of durable antibody responses in antigen free settings, specifically exploring a potentially novel niche site conducive to LLPC survival within the liver.

Infrastructure Canada

Funds green infrastructure projects including public transit, energy systems, water/wastewater treatment, and climate adaptation.

Metropolitan Museum of Art

Hot water heating piping system will be tested, chemically flushed and replaced as required throughout the building.

U.S. National Science Foundation

Infrastructure Systems and People

NIA - National Institute on Aging

PROJECT SUMMARY/ ABSTRACT Iron deficiency is the most common micronutrient deficiency worldwide, affecting 25% of the population. In older adults with heart failure (HF), its prevalence ranges from 40–50% and is associated with worse health status, functional limitations, and increased risks of hospitalizations and death. Once considered only a reversible cause of anemia, iron deficiency is now recognized as an independent comorbidity in HF, even without anemia. Intravenous (IV) iron has proven effective in improving health status and functional capacity in HF with reduced ejection fraction (HFrEF), and guidelines now recommend IV iron for iron-deficient HFrEF patients. However, patients with HF with preserved ejection fraction (HFpEF)—the fastest-growing HF phenotype, with a higher prevalence of iron deficiency—remain largely excluded from these studies. HFpEF affects over 3 million older adults in the U.S., contributing to poor health status, functional impairment, and hospitalizations. To address this critical knowledge gap, we propose the Iron Needed for Function and Undesirable Symptoms in Elderly with HFpEF (INFUSE-HFpEF) study, a double-blind, placebo-controlled randomized clinical trial of IV iron in 300 ambulatory older patients with HFpEF and iron deficiency. This collaboration among Duke University/Duke Clinical Research Institute (DCRI), Kaiser Permanente Northern California (KPNC), Mount Sinai Health System (MSHS), and St. Luke’s Mid America Heart Institute (MAHI) will evaluate the net clinical benefit of IV iron on patient-centered outcomes, including a composite of death, all- cause hospitalization, and health-related quality of life (QoL), as well as its impact on physical function. The INFUSE-HFpEF study incorporates three innovative approaches. First, it employs a patient-centered strategy by prioritizing patient-reported outcomes such as QoL alongside traditional endpoints, reflecting their growing importance in HFpEF trials and FDA endorsement for regulatory approval. Second, it adopts a pragmatic design with broad eligibility criteria and diverse representation, embedding the trial within routine care and leveraging electronic health records to address gaps in inclusion of older adults, women, and ethnically diverse populations. Third, it incorporates novel physical activity measures as secondary endpoints, using wearable- derived metrics such as step count and gait speed. These measures will be validated against established gold standards, including the 6-minute walk test (6-MWT) and cardiopulmonary exercise testing (CPET) parameters like peak VO₂, aligning with the FDA’s Digital Health Innovation Action Plan. INFUSE-HFpEF will advance understanding of iron deficiency in HFpEF, addressing NIA’s Strategic Goal C-3 to “develop interventions for treating…or mitigating the impact of age-related diseases and conditions.” This trial has the potential to transform care for iron-deficient HFpEF patients, bridging evidence gaps and improving patient-centered and clinical outcomes, while serving as a model for research in aging populations with complex multimorbidity.

NIAID - National Institute of Allergy and Infectious Diseases

Project Summary Multiple sclerosis (MS) is a chronic, autoimmune-mediated disease of the central nervous system characterized by demyelination, axonal loss, and progressive disability. Experimental autoimmune encephalomyelitis (EAE) is an animal model which shares specific particularities with MS, has helped develop current disease modifying therapies (DMTs) used to treat MS patients and has been instrumental to understand mechanisms behind disease development and progression. While current disease modifying therapies have been beneficial to improve the health of MS patients, a significant proportion of them continue to experience relapses, and disease tend to worsen over time suggesting the inflammatory and autoimmune response could be sustained in the CNS. Memory CD4+T cells and B cells have been implicated in the pathogenesis of MS. While most memory T cells can be sampled in the blood because they circulate between lymphoid tissues, blood and non-lymphoid tissues; and their egress from lymphoid tissues and migration to the CNS can be stopped by DMTs, a small fraction of memory T cells called tissue resident memory T cells (TRM) have unique proprieties and resides in non- lymphoid tissues. T cells with TRM phenotype have been identified in the CSF and CNS of individual with from MS. We hypothesize that CNS CD4+ TRMs form a reservoir of autoreactive T cells in the CNS which sustains disease and is poorly targeted by disease modifying therapies directed against circulating T cells. Using a newly developed TRM dependent model of EAE and a targeted CRISPR screen, we will: 1) Identify molecular cues that inhibit TRM maintenance in the CNS during EAE, 2) Validate individually the effect of selected genes on TRM maintenance and EAE progression. Our approach is poised to identify novel inhibitory genes for TRM and therefore could provide the basis for the development of new MS therapies which could work independently or in conjunction with current DMTs. In addition, our findings will provide novel fundamental information regarding TRM and means to inhibit them.

Northern Manhattan Improvement Corporation

Provide all equipment , furniture, fixtures, and data, security and phone systems for new rented space at 45 Wadsworth Avenue.