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Role of Force-directed Lipid Metabolism in the Endothelial-to-Hematopoietic Transition

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NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract In vertebrates, self-renewing hematopoietic stem cells (HSCs) are produced from a developmental event called endothelial-to-hematopoietic transition (EHT). EHT consists of a cellular and transcriptional reprogramming that allows hemogenic endothelial cells (HECs) from a subset of embryonic arteries to leave the vessel and become blood stem cells. HSCs have the capacity to replace and restore the complete blood system upon transplant, making HSC transplant the only curative therapy available for blood diseases like leukemia and lymphoma. Given this therapeutic need, great effort has focused on the development of in vitro protocols that attempt to recapitulate the conditions of EHT for clinical expansion or de novo production of stem cells in the dish. To date none efficiently produce long-lived multipotent HSCs, suggesting that one or more developmental signals for this process remain to be defined. Mechanical forces from blood flow are an essential cue for HSC production via EHT, and the zebrafish Danio rerio provides an excellent animal model in which to study this contribution to hematopoiesis due to conserved molecular genetics of EHT in this species and the ability to observe live embryos with active circulation. Flow-driven EHT is mediated in part by the Yes-associated protein (YAP) transcription factor (TF), a transcriptional coregulator that has roles in organ growth, nutrient regulation and cell fate specification. YAP can be directed to the nucleus as a direct result of physical forces acting on the cell, but the molecular mechanisms by which this promotes EHT and HSC production are unclear. In preliminary data generated under K01 support, single-cell transcriptional analysis of wildtype, yap -/- and YAP-overexpressing HECs from zebrafish point to a role for YAP in regulating a battery of self-renewal hematopoietic TFs, cell cycling and metabolic processes. In examining these YAP gain- and loss-of-function (GOF/LOF) transcriptomes, gene module scores suggest an impaired glycolysis-to-oxidative phosphorylation rewiring in HECs. Genes related to lipid metabolism are also dysregulated by YAP perturbation and can be identified in ‘no flow’ datasets from mouse models. This R03 application will investigate the role of force-directed lipid metabolism in developmental EHT using zebrafish as a model. We hypothesize that hemodynamic forces alter lipid usage in HE to drive the metabolically intensive process of EHT. In the first aim, an unbiased approach of mass spectrometry-based lipidomic profiling will be used to quantify the abundance of lipid species in wildtype and YAP gain or loss of function (GOF/LOF) whole-embryo and sorted endothelial cell populations to determine those metabolites that are YAP-regulated (as a proxy for a major cellular transducer of mechanical force). In the second aim a candidate pathway, the secreted sphingosine-1-phosphate lipid mediator, will be studied for its role in EHT by live-imaging, chemical perturbation and state-of-the-art genome editing technologies to create tissue-specific LOF zebrafish lines. Findings from this proposal will uncover force-driven metabolic responses that might enhance production of HSCs via EHT and generate critical preliminary data to support R01 applications.

Up to $128K
2027-12-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Roles of Misfolded Protein Aggregates on Latent Reservoirs in SIV-infected, ART-treated Aged Rhesus Macaques

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NIA - National Institute on Aging

Abstract The advancement of combination antiretroviral therapy (ART) has improved the lives of people living with HIV (PWH) to manageable diseases. However, due to the persistence of viral reservoirs, a cure for HIV remains elusive. Chronological aging is associated with cerebral and extracerebral progressive accumulation of amyloid fibrils, which plays a crucial role in the development of late-onset Alzheimer's and Alzheimer's disease-related dementias (AD-ADRD). More than ten precursor proteins, including transthyretin, amylin, lactadherin, Aβ1-42, α- synuclein, epidermal growth factor-containing fibulin-like extracellular matrix protein 1, semenogelin, and others, are implicated in age-associated amyloidosis. Age-associated amyloidosis results in activation of microglia in the brain, T cells and myeloid cells in the periphery, M1 polarization of macrophages, and creates a systemic chronic inflammatory milieu. In the United States, more than half of all the people living with HIV (PWH) are aged 50 years or older. Additionally, more than 15% of newly HIV diagnosed Americans are over 50 years of age. Therefore, it becomes paramount to understand the impact of amyloid fibril deposition on the reactivation and expansion of lymphoid and myeloid latent reservoirs in older people living with HIV. Conversely, HIV infection and chronological aging are two mutually exclusive comorbid conditions for the development of AD-ADRD. Therefore, it is indispensable to understand the role of HIV in enhancing the deposition of amyloid fibrils and in the development/acceleration of AD–ADRD among older people living with HIV. The commonly used small animal models of AD, not comprehensively recapitulate the heterogeneous manifestations of late onset of AD. On the contrary, rhesus macaques naturally develop age-associated cognitive decline and deposition of amyloid fibrils closely mirrored in humans. This proposal aims to address the knowledge gaps in the field described above. In Aim 1, we will study the impact of age-associated deposition of amyloid fibrils on HIV reservoirs, and in Aim 2, assess the impact of viral infection on the enhancement of chronological aging-associated amyloidosis, and subsequent development of AD-ADRD phenotypes. We anticipate that understanding the aging-associated reactivation and expansion of the viral reservoir will help to provide a more informed approach to designing HIV cure research interventions for older people living with HIV, as well as understanding the role of HIV on the development of late-onset AD-ADRD will aid in the development of customized care modalities, including treatment for comorbid conditions.

Up to $422K
2028-05-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Same-Day Antiretroviral Therapy as a Behavioral Design Intervention to Reduce Stigma in Key Affected Populations

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

Peru's HIV epidemic is concentrated in MSM, where high rates of stigma and discriminaton toward them have undermined treatment outcomes. Despite high diagnostic and linkage rates, MSM have low levels of ART initiation and viral suppression related to low retention in care. For MSM with HIV, multi-dimensional stigma related to sexual orientation, substance use disorders, sex work, multiple sexual partners, etc. undermine treatment efforts through numerous clinical interactions that have the potential to reinforce stigma and delay ART initiation. This grant proposes a transformative approach to reduce HIV-related stigma through a Behavioral Design Intervention (BDI) that utilizes same-day ART (SD-ART) protocols to streamline the treatment initiation process. Unlike other stigma-reduction interventions, BDIs operate at the organizational level, rather than at the clinician or patient level. Our strategy builds upon robust evidence that rapid-start ART (RS-ART) significantly increases ART initiation, retention and viral suppression, thus improving individual and public health. To address the entrenched stigma and operational barriers that persist in treatment initiation, this research will deploy innovative methodologies and technologies. We will first develop a tailored SD-ART protocol utilizing asynchronous online focus groups and flowcharting techniques to map the current ART initiation process and design a streamlined SD-ART protocol. This protocol will use choice architecture to streamline the ART initiation process by minimizing clinical interactions that can reinforce stigma. Using nominal group techniques (NGT), a mixed methods strategy, we will assess multi-level barriers and facilitators to SD-ART from the perspectives of patients (MSM), clinicians, and administrators. From this process, scripts for framing and nudging will be created to inform refinements to the SD-ART protocol to ensure it addresses the specific needs of MSM and thereby enhancing its effectiveness and acceptability. The SD-ART protocol tailored to MSM using behavioral design will be pilot-tested with 125 newly diagnosed MSM. This phase will include longitudinal dyadic analyses to measure changes in stigma, physician trust, social support, and psychological well-being. These insights will not only assess the protocol's impact but also guide further improvements, paving the way for a future implementation trial. Our approach is distinctively designed to reduce the stigma experienced by MSM in clinical settings. By restructuring the decision-making process to prioritize clinical indicators over subjective assessments, our intervention aims to foster a more supportive and non-discriminatory healthcare environment. We hypothesize that this will decrease both perceived and enacted stigma, thereby improving patient-level health outcomes while reducing negative stereotypes by clinicians as MSM succeed in their treatment. By integrating behavioral design into the ART initiation trajectory, this project represents a novel approach to addressing the complex challenges of HIV treatment in high-stigma contexts, offering significant potential for replication and scalability elsewhere.

Up to $57K
2029-03-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Scanco nano/microCT system

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OD - NIH Office of the Director

Three-dimensional imaging of preclinical and clinical samples to assess the amount, shape and quality of tissues is essential for research studies in musculoskeletal biology, regenerative medicine, and other fields. One established imaging technique for non-destructive assessment of specimens is microcomputed tomography (microCT), which utilizes the differential attenuation of X-rays by various tissues to provide high resolution (0.5 to 10 ìm) 3D images and to facilitate quantification of tissue morphology. MicroCT has been used extensively to characterize bone density and bone morphology, and is an indispensable tool for investigators in a variety of fields, including musculoskeletal biology, developmental biology, fracture healing, organ cross-talk, tissue engineering and regenerative medicine. Advances in imaging technology and contrast agents now allow the use of microCT for characterization of non-mineralized tissues (e.g. cartilage, tendon, & blood vessels), enabling broad usage of this technology. Here we propose to purchase a cabinet, cone beam, ultrahigh-resolution nano/microCT system (ìCT50, Scanco Medical AG). This advanced system acquires images at voxel sizes ranging from 0.5 to 100 ìm and can accommodate sample sizes up to 105 mm in diameter and 120 mm in height. The system is capable of high-throughput imaging due to an integrated automated sample changer, large X-ray detector and powerful computer workstation. The system will benefit a large group of 11 major and 14 other/minor users who have a track record of using microCT to advance their research. These investigators are funded by 23 current NIH research grants from 7 different NIH institutes (NIAMS, NIDDK, NICHD, NIA, NHLBI, NINDS, and NIDCR). The projected usage of the system by NIH-funded investigators is 90% of the accessible use time (AUT, 69% by major users and 21% by other/minor users). The new scanner will be replacing a 17-year-old microCT system that will no longer by supported by the manufacturer due to lack of access to replacement parts (including the x-ray tube, a critical component of the system). Furthermore, the computer workstation required to operate the machine is no longer produced, and any future repairs and service would need to be sourced by a 3rd party vendor. With strong institutional support, this new state-of-the-art nano/microCT system will be embedded in the Translational Imaging and Phenotyping Core, which is part of the NIH P30-funded Center for Musculoskeletal Research. Importantly, the PI has extensive expertise in use of this technology and has successfully operated this imaging core for over a decade. Altogether, the acquisition of a new nano/microCT system via this shared instrumentation grant will have an immediate and sustained benefit to investigators in the greater Boston area and beyond.

Up to $425K
2027-05-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Schottky Field Emission Scanning Electron Microscope (FESEM) with serial block-face imaging for a multi user core imaging facility

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OD - NIH Office of the Director

PROJECT SUMMARY/ABSTRACT This application is a shared instrumentation grant from the Analytical Imaging Facility (AIF) at the Albert Einstein College of Medicine to acquire a new, advanced field emission scanning electron microscope (FE-SEM) with the ability to perform serial block-face imaging (SBF-SEM). The AIF supports many investigators at Einstein (143 Principal Investigator Laboratories in 2024), including many NIH funded investigators, by giving them access to state-of-the-art microscopy technologies that enhance cutting edge, collaborative, and multidisciplinary research. Since 2011, the AIF has had a Zeiss scanning electron microscope capable of 3D volume imaging with a total usage of 1987 hours from January 2024 through August 2024. Due to the age of the instrument, we have only been able to have a limited service contract on the microscope since 2023. This means that the vendor no longer guarantees availability of parts as part of the contract. The microscope had a component failure in September 2024 that the vendor has been unable to repair due to inability to obtain replacement parts. To continue to support the ongoing NIH funded biomedical research that relies on scanning electron microscopy, we need to replace the failed instrument with a new FE-SEM that can offer all the functions of our failed current microscope, including secondary electron imaging for fine surface detail as well as the capability of 3D volume reconstruction. For 3D volume imaging, the requested microscope has the capability of serial block face imaging. In this method, the sample surface is imaged, then a thin slice is removed, then the next image is acquired, resulting in the serial acquisition of a z-stack of the sample. The AIF has ongoing 3D volume projects for all the Major Users in this application. New image acquisition has been halted since the microscope has been down for 8 months. During this period, the AIF staff have been concentrating on image analysis of the collected data by developing expertise in segmentation and presentation of 3D models. A new microscope is urgently needed to enable these projects to move forward. Overall, acquisition of this advanced instrument will have a high impact on the NIH-funded biomedical research at Einstein, including the following major and minor user projects: fine structural aspects of atherosclerosis (Dr. Raiscos-Bernal), cardiovascular disease (Dr. Sibinga), spermatogenesis (Dr. Jenny), cellular response of cytotoxic chemotherapy on lymphoid organs (Dr. Karagiannis), autophagy (Dr. Singh), neurodegenerative disease (Dr. Willis) and diabetes (Dr. Santulli). There are also additional four minor user projects and 6+ labs currently using traditional (secondary electron surface imaging) scanning electron microscopy here at Einstein that will benefit from this technology.

Up to $750K
2027-05-15
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

SEAL (Stopping Atopic dermatitis and ALlergy) Study: Prevent allergy by enhancing the skin barrier

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NIAID - National Institute of Allergy and Infectious Diseases

Project Summary and Abstract for the SEAL (Stopping Eczema and ALlergy) Study Food allergy (FA) is an epidemic among children in the U.S., U.K., and other countries. There is increasing evidence that epicutaneous allergen sensitization through a dysfunctional skin barrier results in allergic responses whereas early consumption of food allergens induces oral tolerance, as described by the dual allergen exposure hypothesis. In the Learning Early About Peanut LEAP and Enquiring About Tolerance (EAT) studies, dry skin and the severity and the duration of eczema or atopic dermatitis (AD) in the 1st year of life were predictors of peanut allergy (PA) and sensitization. In the SEAL study, we aim to intervene very early in a high-risk infant group, as soon they have the earliest onset of dry skin or eczema in the 1st 10 weeks of life, but before they have developed allergies. By reducing the duration and severity of eczema and preventing eczema exacerbations, we aim to prevent epicutaneous allergen sensitization and significantly reduce the incidence of FA. Our primary objective is to test if the combination of trilipid skin emollient use early in life with proactive topical steroids decreases the prevalence of FA compared to controls. We propose a randomized (1:1), controlled trial design for infants with dry skin or eczema (n=750 total) to compare the effect of proactive treatment against a reactive treatment group for the prevention of FA, by reducing dry skin, and the severity and duration of eczema in early infancy. We will test our hypothesis with the following specific aims using world-class clinical research units known for excellent recruitment and retention of patient cohorts, mechanistic testing, and state of the art research. Specific Aim 1: To determine if proactive versus reactive treatment will reduce the occurrence of FA in a prospective, randomized, and controlled intervention trial of infants with eczema. Specific Aim 2: To test whether the skin of children in the proactive treatment will show improved epithelial barrier markers with increased commensal bacteria colonization. Specific Aim 3: To determine whether proactive treatment will be associated with protective immune responses. If the aims are achieved, our proposal will make a clinical impact by providing a new, clinical strategy to prevent the occurrence of FA in young infants that present with the earliest signs of dry skin or eczema.

Up to $205K
2027-05-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Selective vulnerability of the locus coeruleus and hypothalamus to HSV-1 infection in Alzheimer's disease progression

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NIA - National Institute on Aging

PROJECT SUMMARY. Alzheimer's disease (AD) is characterized not only by progressive memory loss but also by a range of non- cognitive deficits, including sleep disturbances and autonomic dysfunction. Emerging evidence implicates herpes simplex virus type 1 (HSV-1) as a critical environmental trigger that accelerates AD pathology. Our preliminary data demonstrates that HSV-1 preferentially infects the locus coeruleus (LC) and paraventricular nucleus of the hypothalamus (PVN) in both wild-type (WT) and AD mouse model mice—key regulators of non- cognitive functions—to induce early amyloid deposition, tau hyperphosphorylation, and neuroinflammatory responses, ultimately exacerbating AD progression. Furthermore, HSV-1 exacerbates microglia dysfunction and amyloid accumulation in AD mice. These observations raise a critical question: does HSV-1 infection initiate early transcriptional and post-translational changes in the LC and PVN that accelerate physiological and behavioral deficits? In this proposal, we hypothesize that HSV-1 induces Aβ and NFT formation in the LC and PVN, triggering a hyperinflammatory response prior to hippocampal involvement. To test this hypothesis, we will employ an integrated, multidisciplinary approach using advanced spatial transcriptomics and proteomics (via the NanoString GeoMx DSP platform) alongside in vivo electrophysiological (EEG/LFP) and behavioral assays (using FED3 feeding devices). Aim 1 will delineate the spatial and temporal molecular alterations in the LC and PVN following intranasal HSV-1 infection in 3xTg AD mouse models and WT controls. This analysis will focus on the regional accumulation of amyloid and tau pathologies, microglial activation, and associated gene expression changes that precede hippocampal involvement. In Aim 2, we will link these molecular changes to functional outcomes by monitoring disruptions in LC activity, sleep-wake cycles, EEG rhythms, and feeding behavior. This study is innovative in its use of state-of-the-art spatial omics combined with rigorous neurophysiological and behavioral assessments to bridge the gap between molecular pathology and functional deficits in AD. The outcomes are expected to provide critical insights into HSV-1's role in triggering early AD pathogenesis, particularly in non-cognitive domains, and may identify novel targets for early intervention. Ultimately, this research will help reshape our understanding of viral contributions to neurodegenerative processes and inform the development of therapeutic strategies aimed at mitigating both cognitive and non-cognitive symptoms of AD.

Up to $442K
2028-05-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

Shaping the Future of Cardiovascular Medicine: Integrating Basic Science Breakthroughs to Clinical Impact

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NHLBI - National Heart Lung and Blood Institute

ABSTRACT This proposal requests NHLBI support for the 2026 Scientific Sessions meeting presented by the Council on Basic Cardiovascular Sciences (BCVS) of the American Heart Association (AHA). This meeting has become the “go to” meeting for basic and translational cardiovascular sciences by providing opportunities for established and emerging investigators to present their work and receive constructive feedback. The meeting in 2026 represents the 21st consecutive annual conference. Funding for BCVS Scientific Sessions from National Heart, Lung and Blood Institute (NHLBI) has been secured for 17 of the last 19 years. The BCVS summer conference is entitled “Shaping the Future of Cardiovascular Medicine: Integrating Basic Science Breakthroughs to Clinical Impact”. In 2025, our in-person conference was a rousing success with about 1,000 investigators from around the world. We plan to again hold an in-person meeting in 2026 to help facilitate the careers and networking opportunities for young investigators and support collaborations. The meeting is scheduled for July 13-July 16, 2026 and will begin on a Monday and run through Thursday. The conference will highlight the newest basic and translational cardiovascular research with implications for cardiovascular health and disease. There will be approximately 14 scheduled state-of-the-art sessions that include a mix of established and emerging investigators. The 2026 BCVS keynote address will be given by Dr. Johnathan Epstein, a Robert G. Dunlop Professor, who serves as Dean of Perelman School of Medicine and Executive Vice President of the University of Pennsylvania for the Health System. There are specific sessions for early career scientists, including two early career sessions, an Early Career Keynote Lecture, and the Outstanding Early Career Investigator Award Competition. We will host special sessions for networking including interactions with journal editors and staff. We will also include a Networking Breakfast to support scientists. This R13 proposal is designed to provide support to young investigators to enable their participation in the meeting as presenters either in oral or poster format. The primary organizers are Drs. Farah Sheikh and Jennifer Davis. The Program Committee (11 members) includes the past program co-chair and leadership from across the US drawn from the many disciplines encompassed by BCVS. The AHA will continue to provide its outstanding administrative support with dedicated staff for the logistics of the conference. We fully anticipate that this team will coordinate an exceptional 2026 BCVS conference.

Up to $15K
2027-05-31
health research

Free to search & build · $99 one-time to unlock the application pack · No subscription

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