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DIAPH1, Macrophages and Atherosclerosis

Award Number: F31HL182260
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/11/2026
PERIOD OF PERFORMANCE END DATE: 12/10/2027

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DIAPH1, Macrophages and Atherosclerosis - Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,425 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cardiovascular Diseases Research	000	1	6/16/2026	NEW	$43,425
														Subtotal = $43,425

Grand Total All Awards = $43,425

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DIAPH1, Macrophages and Atherosclerosis

Award Number: F31HL182260

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/11/2026

PERIOD OF PERFORMANCE END DATE: 12/10/2027

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