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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.

National Institutes of Health

Innovation Grants to Nurture Initial Translational Efforts (IGNITE): Development and Validation of Model Systems to Facilitate Neurotherapeutic Discovery (R61/R33 Clinical Trial Not Allowed)

SYSTEM INNOVATORS DIV/N. HARRIS COMPUTER

Information Technology Broadcasting and Telecommunications

Environmental Conservation

Installation of a new 294,200 gallon distribution storage tank with a mixing system and booster pump

Morris

Installation of Security Camera System at Transfer Station

U.S. National Science Foundation

Integrated Data Systems & Services

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY The increasing frequency of respiratory infectious diseases, such as influenza and COVID-19, which can spread rapidly and lead to severe outbreaks, necessitates that we re-envision our approaches to monitor pathogen exposures in the indoor environments. Current surveillance methods mostly depend on syndromic data from hospital admissions, clinic visits, and school absenteeism rates. However, these approaches can lead to underestimation and delay in disease surveillance due to no reporting of mild or asymptomatic cases, lack of access to healthcare, and time-consuming lab and diagnostic processes. A proactive approach in combating airborne diseases requires early detection of target pathogens. Here, we propose to innovate an intelligent system capable of real-time, efficient, and cost-effective monitoring of airborne pathogens in the environment. We will build upon our preliminary success in automated bioaerosol sampling and pathogen detection, to create an Airborne Pathogen Sensing (APS) system. This goal will be achieved by focusing on two specific aims. First, we will create a novel class of modular whole-cell biosensors for sensitive, rapid, and robust detection of multiple critical airborne pathogens. The pathogen detection will be achieved by creating quenchbody (Q-body) display biosensors, where target specific quenchbody is expressed and displayed on the surface of microbial host cells. When the Q-body binds to its antigen (target pathogen), the fluorescence intensity substantially increases via the antigen-dependent removal of the quenching effect on the fluorophore. Second, we will design and build a portable and automated bioaerosol sampling device that can be coupled to the biosensing and signal detection systems. To this end, we will evaluate and optimize two sampling devices: mist chamber and biosampler, and choose the device with the highest bioaerosol capture efficiency. Finally, we will integrate the biosensing component with the bioaerosol sampling device and an automated flow-through fluorescence detection system to achieve automated real-time monitoring of airborne pathogens.

NIA - National Institute on Aging

Project Summary/Abstract Sepsis, the body’s injurious response to infection, afflicts nearly 50 million people worldwide annually with a particularly high burden in older patients. The majority of sepsis survivors experience prolonged or permanent brain dysfunction. We have recently discovered that this form of post-septic impairment is partially driven by a pathologic organ crosstalk between the systemic vasculature and brain, a process that may be exacerbated by age. The endothelial glycocalyx, a heparan sulfate (HS)-rich layer that lines the lumen of all blood vessels, is degraded during sepsis, releasing highly biologically active HS fragments into circulation. These circulating HS fragments selectively deposit within the hippocampus and can worsen cognitive outcomes in sepsis survivors. Strikingly, circulating HS levels are 5-fold higher in older (≥65) compared to younger patients (<50) with sepsis. This aging-associated increase in HS shedding may be due to a more fragile endothelial glycocalyx. In preliminary preclinical studies, we have found that increased age was associated with ultrastructural changes of the glycocalyx, including a loss of 6-O sulfation residues within endothelial-derived HS. Loss of 6-O sulfation is known to increase HS susceptibility to degradation by heparanase, the “sheddase” responsible for glycocalyx degradation during sepsis. This loss of sulfation may be due to increased circulating Sulfatase-2 (Sulf2) an enzyme dedicated to removal of 6-O sulfates from HS as 1) preliminary single cell RNA sequencing of peripheral blood mononuclear cells demonstrated that aged humans have increased levels of Sulf2 in monocytes and 2) aged mice exhibited increased blood Sulf2 activity. Based on these preliminary observations, we hypothesize that age-related remodeling of endothelial HS by monocyte-derived Sulf2 predisposes older patients to release brain-penetrating HS during sepsis, which will be associated with post-septic brain dysfunction. We will rigorously test this hypothesis in both pre-clinical models of sepsis and a prospective, observational cohort of patients with sepsis. We will specifically 1) determine whether age-related increases in expression of Sulf2 in monocytes are responsible for endothelial glycocalyx fragility in older mice; 2) determine whether age-related increases in expression of Sulf2 in monocytes exacerbate pathogenic HS deposition during sepsis in aged mice; and 3) identify whether circulating pathogenic HS fragments are associated with impairment in multiple cognitive domains in older sepsis survivors. This work will mechanistically investigate a unique form of age-related pathologic interorgan communication: release of brain-penetrating, pathogenic HS from the systemic vasculature. Critically, it may also identify Sulf2 inhibition as a therapeutic target in sepsis, which could improve the lives of millions of older survivors per year.

Areion Unmanned Aerial Systems LLC

Interpath flight tests

NIAID - National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY In the healthy intestine, the microbiota and intestinal immune system are intimately linked. One of the major regulators of the microbiome is the mucosal antibody, IgA, produced by intestinal B cells, which exerts unique immunomodulatory functions on bacterial communities. Failures in bacterial regulation by IgA has serious health implications, impacting the progression of a wide range of diseases like inflammatory bowel disease (IBD), obesity, cancer, and depression. However, whilst many studies have identified roles for IgA in bacterial regulation, how the presence of the microbiota directs differential programming of local B cell responses towards production of regulatory IgA is poorly understood. Most homeostatic IgA is produced via gut-associated germinal centers (gGCs), microanatomical niches which are essential for B cell and antibody evolution. Although we have previously shown that gGCs support effective selection of microbiota-specific B cell clones, accumulating evidence indicates that fundamentally altered signaling networks govern the dynamics of steady-state gGCs. In our preliminary data we identify composition of the microbiota as a significant modulator of several aspects of gGC responses, suggesting a crosstalk that is established between the intestine, B cells, and the microbiota. We therefore hypothesize that ‘education’ in the intestinal microenvironment by the microbiome fundamentally alters how B cells to evolve in gGCs. We show evidence that the responsiveness of several immunoreceptors is modified following exposure to the microbiome, suggesting that chronic bacterial stimulation broadly desensitizes receptor function and sets lowered activation thresholds. Commensals are perceived by cells specifically through the B cell receptor (BCR) and via generic sensing through Toll-like receptors (TLRs). We present new evidence supporting that sustained stimulation by TLR ligands acts as a signal rheostat, tuning inherent responsiveness of B cell receptor and CD40 signaling networks to regulate permissive entry to chronic gGCs. Consequentially, TLR deficient animals host enlarged gGCs, in direct opposition to inflammation-driven GCs, which are severely compromised in the absence of TLR activation. We propose a model whereby continuous low-level TLR signaling in combination with weak BCR binding could be sufficient to initiate gGCs towards the microbiome, facilitating the selection of a regulatory pool of IgA with broad binding specificity. We will test our hypotheses through use of two specialized imaging approaches, a novel commensal-specific transgenic BCR mouse model, and restricted-diversity microbiomes, to address how exposure to microbial signals tunes the magnitude and specificity of intestinal B cell responses. Our studies will further our understanding of the mechanisms driving dysregulation of the microbiome, important for autoimmunity, cancer, and metabolic disorders. Results from our proposal will also generate valuable insights into the rules governing tissue-specific antibody responses and IgA memory, a rapidly emerging interest area in mucosal infectious disease research.

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT: Our laboratory discovered and confirmed STING (Stimulator of Interferon Genes) as an essential component of the cytosolic DNA-mediated innate immune response pathway. We subsequently demonstrated that STING signaling is commonly suppressed in microbial infected cells or human cancers, which enable such cells to escape the host immunosurveillance system. Our new data, enclosed herein, indicates that intrinsic innate immune STING signaling stimulates the production of essential innate immune proteins that in combination with microbial or self-nucleic acid, renders such cells highly immunogenic. Here, we intend to clarify the mechanisms of how intrinsic STING signaling facilitates the trans-activation of phagocytes and the cross-presentation of microbial or tumor antigen. Aim I: We aim to evaluate the mechanisms by which innate immune STING signaling renders microbial infected cells or DNA-damaged cells immunogenic, compared to normal apoptotic cells (which are non-inflammatory). Our data indicates that cytosolic DNA triggered STING-inducible genes combine with and protect, cytosolic DNA species to enable them to escape DNase-mediated degradation and activate STING signaling, in trans, in engulfing phagocytes. We have now identified these genes and will further characterize their novel mechanisms of action. Aim II. Our data indicates that innate immune STING signaling is suppressed in aged cells by epigenetic silencing. Such cells, for example, STING -/- MEFs or transformed cells lacking cGAS or STING expression, are non- immunogenic following DNA-damaging events, even though they produce cytoplasmic micronuclei. We hypothesize that reconstituting intrinsic STING signaling in vitro and, in vivo, will render cells immunogenic and trigger the innate activation of engulfing phagocytes. We believe that these strategies could shed insight into mechanisms of resistance to cancer therapies, (many of which invoke micronuclei formation) as well as lead to new strategies to help improve the treatment of a wide array of inflammatory and malignant disease.

NIA - National Institute on Aging

Frontotemporal dementia caused by mutations in microtubule-associated protein tau (MAPT), including the N279K mutation, is a common cause of early-onset dementia. It is neuropathologically characterized by toxic aggregation of hyperphosphorylated tau, glial activation, and neurodegeneration. The factors contributing to the disease are likely numerous and poorly understood, and no disease-modifying therapies exist for FTD. Oxidative stress (OS) occurs when a cell’s innate antioxidant system is overwhelmed by reactive oxygen species, and oxidative modifications of biological molecules have important consequences on protein, DNA, and lipid function. In particular, uncontrolled lipid peroxidation can lead to ferroptosis, a specific cell death pathway which we found to be enriched in FTD postmortem brain and may contribute to neurodegeneration. We also identified an OS and neuroinflammatory phenotype in postmortem brain from FTD patients and induced pluripotent stem cell (iPSC)-derived neurons from FTD patients. Specifically, FTD iPSC-derived neurons show upregulation of the gene secreted phoshoprotein-1 (SPP1) and its protein product osteopontin (OPN), which can activate iPSC-derived microglia in vitro. Given the centrality of OS in our FTD models and the apparent association with SPP1, this proposal seeks to investigate mechanisms of OS generation and downstream sequelae in FTD. In aim 1, I will interrogate the effects of different classes of oxidative and ferroptotic stressors on FTD MAPT N279K iPSC-derived neurons. In aim 1a I will assess cell viability and lipid peroxidation. In aim 1b I will assess tau pathology and neurite outgrowth. In aim 1c I will attempt to rescue any effects seen in aims 1a and 1b by co-treating with antioxidant and ferroptosis inhibiting compounds. In aim 2 I will characterize astrocyte-neuron crosstalk in the FTD context. First, in aim 2a I will generate iPSC-derived astrocytes from FTD MAPT N279K patients or healthy control patients and treat with OPN and assess for astrocyte reactivity. In aim 2b I will generate antioxidant response gene reporter astrocytes and treat with Ctrl or FTD neuron conditioned medium to determine the role of neuron-secreted factors in astrocyte response. Finally, in aim 3 I will explore the potential of targeting OS in FTD. I will xenotransplant FTD or Ctrl neural progenitor cells into mice forebrains and treat systemically with liproxstatin, an antioxidant and ferroptosis inhibiting compound. In aim 3a I will characterize proteins involved in these pathways as well as glial reactivity and graft survival by histology. In aim 3b I will perform snRNA-seq on micro dissected grafts to map changes in gene expression profiles in response to OS targeting.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary/Abstract Myelin is a lipid-rich sheath that wraps axons within the vertebrate nervous system to increase the speed of action potential propagation and provide metabolic support to the axon. The myelin sheath is generated by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Developmental myelination is a dynamic and complex process. Some of the cellular interactions driving myelinating glial cell development have been characterized, but a full understanding of the molecular mechanisms that mediate this process is lacking. Genetic disorders affecting the white matter, termed leukodystrophies, result in absent or abnormal myelin development, and are most often diagnosed in infants and children. On the other hand, demyelinating disorders, such as multiple sclerosis, involve the breakdown of existing myelin and can be caused by direct destruction of the oligodendrocyte or occur as a result of neuronal damage or degeneration. All of these disorders can lead to cognitive defects, muscle weakness, motor problems and more. Treatments are limited, and efforts are underway to better understand the mechanisms driving myelin development in order to develop remyelinating therapies. Using publicly available RNA sequencing and proteomics data, the gene cd59 was identified as highly expressed in Schwann cells and oligodendrocytes during development. Cd59 encodes the small GPI-anchored protein Cd59, which is best known for inhibition of complement-induced cell lysis of host cells. Recent studies have also implicated a non-GPI anchored isoform of Cd59 in facilitation of SNARE complex assembly and exocytosis in various cell types. The Kucenas lab generated cd59 mutant zebrafish using CRISPR-Cas9 genome editing and found that Schwann cells of cd59 mutant larvae over-proliferate but display hypomyelination and disrupted node of Ranvier development. This proposal aims to decipher the role of Cd59 in oligodendrocyte development. Aim 1 will further investigate the presence of paranodal bridges linking individual myelin sheaths as seen in preliminary studies and will examine the development and maturation of nodes of Ranvier in cd59 mutants. Aim 2 will focus on understanding the mechanisms by which Cd59 regulates oligodendrocyte development, investigating the role of Cd59 in oligodendrocyte exocytosis and whether this is mediated by a non-GPI anchored isoform as shown in other cell types. This proposal will be conducted in the Kucenas lab at the University of Virginia (UVA). The Kucenas lab has a strong track record of discovering novel mechanisms of glial cell development, and UVA is well known for its expansive glial biology community. Completion of this fellowship will include a mastery of various technical skills, such as molecular biology and advanced microscopy, and drive intellectual and professional growth as an independent scientific researcher.

NINDS - National Institute of Neurological Disorders and Stroke

Project Summary Circumventricular organs (CVOs) are specialized brain regions with unique vascular properties, lacking the classical blood-brain barrier (BBB), to facilitate rapid communication between the brain and periphery. Among these, the median eminence (ME) plays a central role in regulating vital neuroendocrine processes such as hunger, stress, and reproduction. Unlike other CVOs, tanycytes, a specialized ependymoglial cell type, establish a selective barrier between the ME, cerebrospinal fluid, and CNS parenchyma. However, how this barrier is formed, its distinct features compared to other CVOs, and its response to systemic and CNS inflammation remain poorly understood. This project seeks to define the molecular and cellular mechanisms underlying tanycyte barrier formation and its functional role in the ME. Specifically, it will investigate the role of Claudin-10, a key tight junction protein, in maintaining barrier integrity and regulating ion permeability. Additionally, the project will explore how inflammation disrupts tanycyte-mediated barrier function and how such changes affect hypothalamic regulation. These findings will provide critical insights into the dynamics of CNS barriers and their impact on neuroinflammatory and metabolic disorders, offering potential avenues for therapeutic interventions.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Eosinophilic esophagitis (EoE) is a newly described immune-mediated disease and a leading cause of esophageal morbidity in children and young adults. Histologically, pediatric EoE is characterized by esophageal basal cell hyperplasia (BCH) and extensive Th2-associated inflammation. Despite many advances in our understanding of the pathophysiology of EoE, the molecular mechanisms leading to the development of BCH and subsequent epithelial barrier dysfunction in pediatric EoE remain to be elucidated. We previously demonstrated that yes-associated protein 1 (YAP), a key transcriptional regulator in the Hippo signaling pathway, is required for the proliferation and differentiation of basal cells in the developing murine and human esophagus. Using novel pre-weaning mouse models of early-onset EoE and 3D organoid culture systems we have been able to study Th2-driven BCH. Our preliminary data demonstrate nuclear enrichment of YAP in the hyperplastic basal cells of a pre-weaning transgenic mouse model of EoE and esophageal biopsy samples from a pilot study of an EoE patient cohort. In parallel an exploratory untargeted proteomics approach, using human esophageal basal cells (EPC2) cells treated with IL-13 demonstrated that Tenascin-C (TNC), a matrix protein enriched in the basement membrane underlying the hyperplastic basal cells, was among the top-enriched proteins in EPC2 cells upon IL-13 treatment. Moreover, we demonstrated TNC/YAP double-positive cells in our preclinical EoE mouse models as well as increased expression of CD74 in a subpopulation of hyperplastic esophageal basal cells of EoE patients. Based on these findings, the overarching hypothesis is that YAP mediates IL-13-induced CD74 expression, which promotes chronic inflammation characterized by BCH and epithelial barrier dysfunction in pediatric EoE. In Aim 1, we will use YAP loss-of-function mouse models and CD74 inhibitors to test the hypothesis that CD74 activation promotes BCH. In Aim 2, using in vivo and in vitro assays, we will elucidate how CD74 affects the epithelial barrier integrity in the pathogenesis of pediatric EoE. Overall, findings from the proposed studies will significantly advance our understanding of the pathophysiology of pediatric EoE and provide new insights into potential biomarkers and novel therapeutic targets for pediatric EoE.

City of Jacksonville

Jacksonville Water System Improvements

HARRIS CORRECTIONS SOLUTIONS INC

Information Technology Broadcasting and Telecommunications

Friends of Cypher Cafe

The Jefferson Community Center Mock Trial Team will host events that serve as outreach to potential youth participants while providing the community with valuable, accessible information about the judicial system, legal rights, and legal issues that touch our community. Activities will include: producing an educational video; attending competitions; and hosting informative community events and celebration.

City of Richmond

JD SYSTEMS LLC

Office of Addiction Services and Supports

The OASAS Job Placement Initiative offers specialized employment and career services for individuals in treatment for substance use disorders. The Job Placement services are integral to and supported by the evidence-based vocational rehabilitation counseling process. Job Placement includes person-centered job development and job placement services for recovering individuals who seek employment support while participating in the OASAS-licensed treatment provider system. Specifically, Job Placement Providers offer individualized pre-vocational and transitional job seeking assistance services as needed, and intensive and ongoing employment support services up to 180 days to support the continuum of the addiction recovery process.

Parents for Student Success

On Saturday, April 21st at First AME Church, 1522 - 14th Avenue in Seattle, the 2018 Youth Law Forum will offer 250 young people ages 8 - 18, basic instruction on navigating the juvenile justice system. A series of workshops, discussion groups, and question and answer sessions will be offered by local Police, the Sheriff's office, the Washington State Bar Association, and the UW School of Social Work. The aim is to both teach and engage our youth. Participants will also be able to explore career opportunities in the criminal justice field.