DIAPH1, macrophages and atherosclerosis

Active Project Grant Awarded Last action

Award ID
F31HL182260
Recipient
Awarding agency
Obligated
$86,850

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Originally
Place of performance
New York, NY 10016, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Despite significant advances in the treatment of cardiovascular disease (CVD), atherosclerosis and its consequences remain leading causes of morbidity and mortality. Although females experience relative protection from CVD during pre-menopause, this protection is reduced post-menopause. Our laboratory studies the role of damage associated molecular pattern (DAMP) molecules in the pathogenesis of atherosclerosis. Damps, such as advanced glycation end products (AGES), S100/calgranulins and high mobility group box 1 (HMGB1) stimulate signal transduction through receptors such as receptor for age (RAGE) and its intracellular effector, diaphanous 1 (DIAPH1). RAGE and DIAPH1 are expressed on immune and vascular cells, which are relevant to atherosclerosis. Our laboratory recently made the following discoveries that form the basis of my project: (1) global deletion of DIAPH1 in mice devoid of the ldlr resulted in significant reduction in atherosclerosis in male and female mice, in parallel with reduced expression of inflammatory genes in the aortas versus DIAPH1- expressing controls; and (2) in the presence of RAGE ligands, binding of the cytoplasmic domain of RAGE to DIAPH1 enhances the interaction of DIAPH1 with the mitochondrial gtpase mitofusin 2 (MFN2); this interaction mediates oxidative stress, suppresses oxidative phosphorylation (OXPHOS) and causes mitochondrial dysfunction. To dissect the specific DIAPH1-dependent mechanisms in atherosclerosis, I will focus on cell-specific roles for DIAPH1 in macrophages. My data reveal that female not male mice devoid of myeloid DIAPH1 in ldlr null mice displayed significantly lower plasma concentrations of cholesterol and triglyceride and hepatic triglyceride VS. Myeloid DIAPH1-expressing controls. Preliminary data suggest no SEX differences in aortic sinus atherosclerosis, but % necrotic core/lesion area was significantly lower in female not male mice devoid of myeloid DIAPH1 in ldlr null mice; there were analogous effects on lesion macrophage and smooth muscle content. Experiments in bone marrow derived macrophages (BMDMS) from mice expressing or devoid of DIAPH1 reveal distinct effects in female VS. Male cells. I hypothesize that myeloid DIAPH1 affects atherosclerosis and necrotic core pathology via macrophage cell-intrinsic and macrophage intercellular communications in a SEX-dependent manner. My sponsor and CO-sponsor, DRS. ANN marie schmidt and edward fisher, respectively, are expert in the scientific areas critical to my proposal and have strong mentoring experience. My sponsor, CO-sponsor and I have assembled a scientific mentor team, including DRS. Delbare, garabedian, giannarelli, LI, and ramasamy to support my work. I am confident that I will successfully complete my predoctoral research and be well-poised for postdoctoral research, with emphasis on SEX differences, as a basis for my independent career in CVD.

Transactions

Action Obligated Date
Amendment $43,425
Amendment $43,425
Original award $0

Quick answers

Who received award F31HL182260?

F31HL182260 was awarded to New York University by National Heart Lung and Blood Institute (National Institutes of Health) on December 11, 2026.

How much is award F31HL182260 worth?

$86,850 has been obligated on F31HL182260.

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