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Circadian Regulation of Liver-derived Endostatin

Award Number: F31DK143733
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/20/2026
PERIOD OF PERFORMANCE END DATE: 09/19/2027

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Circadian Regulation of Liver-derived Endostatin - Abstract Proteins secreted from the liver (i.e., hepatokines) are biomarkers and potential therapeutics for metabolic disease. Liver circadian rhythms are critical for metabolic homeostasis, yet circadian control of hepatic protein secretion is an underdeveloped area of research. Our previous proteomics study showed that ~20% of proteins annotated as secreted depend on BMAL1, the main transcriptional activator of the molecular clock. Here, our preliminary data show that endostatin, an C-terminal cleavage product of collagen type 18 a1 chain (Col18a1), is regulated by the liver clock and that its abundance peaks in the circulation during daytime. The precise mechanism and downstream signaling of liver-derived endostatin remains unknown. Notably, recent reports have shown that endostatin, or derivatives of it, can profoundly influence adipocyte metabolism, suggesting endostatin has potential as a metabolic target. The overall objective of this proposal is to determine the mechanism(s) underlying circadian control of hepatic and circulating endostatin and understand how this contributes to circadian regulation of adipose tissue adipogenesis/lipolysis. The central hypothesis is that endostatin is a liver- clock controlled hepatokine that targets adipose tissue adipogenesis/lipolysis in a time-dependent manner through mTORC1 signaling in adipocytes. To test this hypothesis, in Aim 1 we will determine the clock control mechanism in the liver and plasma by investigating rhythmic transcription, ER-golgi trafficking, and extracellular cleavage of COL18A1/endostatin. In Aim 2, we will uncover the time-dependent effect of recombinant endostatin on adipocyte lipid metabolism and determine the mechanism behind its time-dependent effect. These studies will employ in vivo and in vitro experiments utilizing mouse models wherein Bmal1 is ablated in the whole body or in a hepatocyte-specific manner, in concert with techniques in molecular biology. This work will enhance our understanding of endostatin as a potential metabolic therapy and lay a scientific framework to better understand circadian control of hepatic protein secretion. This work can also be extended to chronotherapeutic aspects of treatments involving endostatin, which have already been developed in the context of cancer.


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 = $39,298 )
2026	2026	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/20/2026	NEW	$39,298
														Subtotal = $39,298

Grand Total All Awards = $39,298

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Circadian Regulation of Liver-derived Endostatin

Award Number: F31DK143733

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/20/2026

PERIOD OF PERFORMANCE END DATE: 09/19/2027

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