Monday, April 29, 2024 4/29/2024

Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism

Award Number: F31DK126394
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Project Summary/Abstract: Liver receptor homolog-1 (LRH-1; NR5A2) is a phospholipid-sensing nuclear receptor (NR) expressed predominantly in the liver, pancreas, and ovaries that plays an important role in metabolic physiologies and pathophysiologies. Specifically, it has been characterized to regulate bile acid metabolism, cholesterol homeostasis, and steroidogenesis, and in turn is involved in various disease states such as type 2 diabetes, atherosclerosis, nonalcoholic fatty liver disease as well as a multitude of cancers. These diseases are all risk factors for metabolic syndrome that affects nearly a third of the US population. This represents a significant health concern as individuals diagnosed with metabolic syndrome have increased risk for developing cardiovascular diseases as well as hepatocellular, gastric, and colon cancers; cancers that have been associated with overexpression of LRH-1. This suggests LRH-1 to be a promising therapeutic target for such metabolic diseases and cancers. However, a lack of a wholistic understanding of the receptors regulatory mechanism presents a significant limitation to the success of LRH-1 as a therapeutic target. Similar to other nuclear receptors, LRH-1's activity is tightly regulated via a multitude of pathways including cellular localization, ligand binding, DNA binding, post-translational modifications, and coregulator interactions. Cellular localization is central to these pathways as it determines the receptors milieu and thus available interacting partners. While, multiple nuclear localization signals and nuclear export signals have been identified to facilitate receptor shuttling in and out of the nucleus, there is no information regarding LRH-1 intranuclear trafficking, a key process that directly modulates DNA binding and transcriptional output. This propels the need to develop effective and specific tools to modulate LRH-1 localization and activity. While the use of chemical approaches to probe NRs in metabolism has increased over the years, the use of chemoproteomics in this area remains limited. Proteomic analysis of nuclear receptors remains problematic as they are relatively low abundant and tightly bound to chromatin. As such, there is a need for tools to probe and capture endogenous LRH-1 and LRH-1 transcriptional complexes. I propose the following specific aims to develop and employ LRH-1 specific chemoproteomic tools to elucidate the role of acetylation and a novel coregulator lamina associated polypeptide 2 (LAP2) in regulating LRH-1 intranuclear trafficking and signaling. In Aim 1, I will establish two LRH-1 specific probes to more efficiently modulate and/or capture LRH-1 and LRH-1 transcriptional complexes. These include a biotinylated LRH-1 response element oligo probe and SR1848, small molecule inhibitor of LRH-1 signaling. In Aim 2, I will identify LRH-1 acetylated residues and validate LAP2 isoforms as novel LRH-1 coregulators that coordinate to fine tune LRH-1 intranuclear trafficking and subsequent signaling. Elucidation of this regulatory pathway will directly enhance understanding of LRH-1 signaling driving hepatic cancer and other metabolic diseases.


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 = -$13,774 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	-$1,650
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	6/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$12,124
														Subtotal = -$13,774

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	4/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/22/2022	NON-COMPETING CONTINUATION	-$12,124
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,124
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	4/6/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $33,036 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/23/2021	NON-COMPETING CONTINUATION	$33,036
														Subtotal = $33,036

Issue Date FY: 2020 ( Subtotal = $32,520 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/25/2020	NEW	$32,520
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/25/2020	NEW	$0
														Subtotal = $32,520

Grand Total All Awards = $51,782

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Developing chemoproteomic approaches to decipher the regulatory network of LRH-1, a nuclear receptor implicated in hepatic metabolism

Award Number: F31DK126394

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer