Thursday, November 21, 2024 11/21/2024

Understanding the pathogenesis of elevated androgen induced metabolic dysfunction in females

Award Number: R01HD095512
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Androgen receptor (AR) signaling plays a crucial role in androgen induced metabolic dysfunction in states of elevated androgen in females. However, how AR in the liver contribute to metabolic dysfunction in states of androgen excess, such as in polycystic ovary syndrome (PCOS), is unknown. Hyperandrogenemia is one of the defining features of PCOS, and is often accompanied by hyperinsulinemia and obesity making it difficult to discern the role of androgen signaling in the development of metabolic dysfunction not secondary to impaired metabolic function. Therefore, a model that can isolate the pathophysiological effects of hyperandrogenemia from metabolic changes resulting from obesity is warranted. We observed that elevated androgen through androgen receptor in the liver contributes to impaired metabolic function. We hypothesized that in a setting of high androgen levels: 1) androgen/AR interacts with proteins upstream of AKT to interfere with insulin signaling, thus inhibiting the phosphorylation of forkhead box O1 (FOXO1), leading to increased gluconeogenesis; 2) androgen/AR regulates the cAMP-PKA (glucagon) pathway to increase activity of cAMP response element binding protein (CREB), and leading to increased glucose production; 3) AR acts as a transcription factor regulating Foxo1 and Creb gene expression to increase gluconeogenesis; 4) induced metabolic pathology can be corrected or improved by acute deletion of AR thus pointing the way to therapeutic interventional strategies. We will focus on the role of pathophysiological androgen levels acting via AR in the liver. Approaches will use genetic deletion of AR developmentally or acutely in liver in elevated androgen mouse models. Aim1 will focus on the liver (mouse and human hepatocytes) by defining the role of hepatocyte extranuclear AR in androgen induced metabolic dysfunction. Aim 2 will determine whether nuclear AR is required for androgen induced gluconeogenesis. Aim 3 will focus on whether metabolic dysfunction associated with androgen excess can be corrected or rescued by acute deletion of hepatic AR. Together these Aims will elucidate the role of AR in mediating the pathogenic effects of androgen excess in contributing to female metabolic dysfunction.


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 = -$150,106 )
2025	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	000	5	11/7/2024	NON-COMPETING CONTINUATION	-$150,106
														Subtotal = -$150,106

Issue Date FY: 2022 ( Subtotal = $536,530 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	000	5	6/9/2022	NON-COMPETING CONTINUATION	$536,530
														Subtotal = $536,530

Issue Date FY: 2021 ( Subtotal = $576,345 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	002	4	6/1/2021	NON-COMPETING CONTINUATION	$576,345
2021	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	5/14/2021	NON-COMPETING CONTINUATION	-$360,361
2021	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	001	3	5/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$360,361
														Subtotal = $576,345

Issue Date FY: 2020 ( Subtotal = $375,888 )
2020	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	001	3	7/10/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$589,996
2020	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	5/22/2020	NON-COMPETING CONTINUATION	-$214,108
2020	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Child Health and Human Development Extramural Research	002	3	7/14/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $375,888

Issue Date FY: 2019 ( Subtotal = $618,068 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	5/21/2019	NON-COMPETING CONTINUATION	$618,068
														Subtotal = $618,068

Issue Date FY: 2018 ( Subtotal = $644,571 )
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	8/7/2018	NEW	$644,571
														Subtotal = $644,571

Grand Total All Awards = $2,601,296

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Understanding the pathogenesis of elevated androgen induced metabolic dysfunction in females

Award Number: R01HD095512

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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