Tuesday, July 1, 2025 7/1/2025

Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis

Award Number: R16GM145591
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/10/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis - Abstract Atherosclerosis is the underlying cause of great majority of cardiovascular diseases (CVD) and poses a great threat to public health. Activation of thermogenic adipocytes reduces cholesterol levels and protects against atherosclerosis in animal models. Lower thermogenic adipocyte activity in dyslipidemic patients has been characterized by high plasma triglycerides (TG), low plasma high density lipoprotein cholesterol (HDL-C) concentration and lower uncoupling protein 1 (UCP1) expression. These findings in mice and humans underscore the importance of inducers of the thermogenic adipocyte program as potential therapeutic targets for the treatment of dyslipidemia and CVD. Our published and preliminary data demonstrate that follistatin (Fst) plays an important role not only in adipocyte browning but also in lipoprotein metabolism to regulate TG, total cholesterol (TC), and HDL-C levels. In this proposal, we will test our central hypothesis that Fst-induced adipose browning protects against the development of atherosclerosis. We will test our hypothesis under these Specific Aims: Aim 1: We will determine the role of Fst in adipose browning, lipoprotein metabolism and development of atherosclerosis. We will determine the effects of Fst tissue and systemic overexpression using mouse low density lipoprotein receptor (LDLR)-deficient WT and adipose-specific transgenic (FstAdQTg ) mice, and adeno-associated virus 1 (AAV1)-FST344 injected LDLR-/- mice respectively to determine the role of Fst on i) adipose browning, plasma lipoprotein, TG, and TC levels, ii) tissue (adipose, aorta, and liver), plasma metabolites and iii) gene expression during diet-induced development of dyslipidemia and atherosclerosis. Effect of transient loss of Fst on browning, lipoprotein metabolism and atherosclerosis progression will be analyzed in mPCSK9 injected Fstfl/fl / CreAdQ mice. Aim 2: We will determine the molecular mechanisms by which Fst confer the pro-browning and anti-atherogenic effects. We will test whether arginase 1 (Arg 1)/beta-adrenergic receptor (β-AR)/ p38MAPK/FGF21 signaling pathway confer Fst-induced pro-browning and antiatherogenic action in the three animal models. We will utilize gene aortic lesion and gene metabolite correlation dataset obtained from system genetics approach of atherosclerosis hybrid mouse diversity panel (HMDP) to identify key Fst-regulated genes and metabolites. We will perform comprehensive RNA-sequence analysis, and tissue and plasma metabolite analysis combined with pharmacological inhibition studies to identify novel genes and metabolites involved during Fst-induced adipose browning and its anti-atherogenic actions. Our proposed studies will provide significant novel insights into the pro-browning and anti-atherogenic role of Fst and identify key molecular targets involved in favorably altering lipoprotein metabolism and the development of atherosclerosis. Inhibition of atherosclerosis development by using Fst protein/peptide is an attractive therapeutic avenue. Data obtained after successful completion of this project provide rationale for therapeutic drug design for the treatment of atherosclerosis and enable us to submit highly competitive RO1-like grant applications.


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: 2025 ( Subtotal = $142,373 )
2025	2025	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	4/17/2025	NON-COMPETING CONTINUATION	$142,373
														Subtotal = $142,373

Issue Date FY: 2024 ( Subtotal = $142,373 )
2024	2024	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	6/18/2024	NON-COMPETING CONTINUATION	$14,237
2024	2024	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	3/15/2024	NON-COMPETING CONTINUATION	$128,136
														Subtotal = $142,373

Issue Date FY: 2023 ( Subtotal = $146,802 )
2023	2023	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	3/7/2023	NON-COMPETING CONTINUATION	$146,802
														Subtotal = $146,802

Issue Date FY: 2022 ( Subtotal = $148,820 )
2022	2022	CHARLES R. DREW UNIVERSITY OF MEDICINE AND SCIENCE	1731 E 120TH ST	LOS ANGELES	CA	90059	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	5/6/2022	NEW	$148,820
														Subtotal = $148,820

Grand Total All Awards = $580,368

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Follistatin regulation of energy and lipid metabolism during progression of atherosclerosis

Award Number: R16GM145591

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/10/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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