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A strategy for discovery of endocrine interactions

Award Number: R00HL138193
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/03/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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A strategy for discovery of endocrine interactions - Project Summary/Abstract We developed a bioinformatics framework which uses multi-tissue expression arrays and publicly available resources to statistically rank and functionally annotate endocrine axes. By applying this method to expression profiles within the Hybrid Mouse Diversity Panel (HMDP), we identify many known and several novel inter-tissue circuits. We further show the utility of this approach by uncovering a new adipose-to-skeletal muscle endocrine axis which shows promise as a therapeutic target for metabolic syndrome in both mice and humans. Functional experiments show adipose-derived Lipocalin-5 (LCN5) is sufficient to enhance skeletal muscle mitochondrial activity and gene expression. When overexpressed in a mouse model, the secreted peptide prevents and rescues diet-induced metabolic syndrome as measured by insulin- and glucose- tolerance. We also show that the human orthologue of the protein is sufficient to enhance expression of similar oxidation and biogenesis genes in human muscle cells. We further expand this method to identify adipose-derived Inter α-trypsin inhibitor 5 (Itih5) as a conserved regulator of cardiomyocyte function. Specifically, correlative data in mice and humans and mechanistic studies show ITIH5 as a suppressor of cardiomyocyte hypertrophy. The goal of this proposal is to 1) Mechanistically dissect how Lipocalin-5/6 enhances skeletal muscle mitochondrial activity in mice and humans and 2) Utilize both global and targeted studies to understand biologic processes by which ITIH5 reduces cardiac hypertrophy in a physiologic and pathophysiologic state.


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: 2023 ( Subtotal = -$94,033 )
2023	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cardiovascular Diseases Research	000	5	9/26/2023	NON-COMPETING CONTINUATION	-$94,033
														Subtotal = -$94,033

Issue Date FY: 2022 ( Subtotal = $247,473 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cardiovascular Diseases Research	000	5	2/8/2022	NON-COMPETING CONTINUATION	$247,473
														Subtotal = $247,473

Issue Date FY: 2021 ( Subtotal = $249,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cardiovascular Diseases Research	000	4	2/8/2021	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2020 ( Subtotal = $343,033 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cardiovascular Diseases Research	000	3	11/28/2019	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cardiovascular Diseases Research	001	3	5/6/2020	EXTENSION WITH OR WITHOUT FUNDS	$94,033
														Subtotal = $343,033

Grand Total All Awards = $745,473

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A strategy for discovery of endocrine interactions

Award Number: R00HL138193

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/03/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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