Restricted Research - Award List, Note/Discussion Page

Fiscal Year: 2018

1337  The University of Texas at Arlington  (74842)

Principal Investigator: Subhrangsu s Mandal

Total Amount of Contract, Award, or Gift (Annual before 2011): $ 439,360

Exceeds $250,000 (Is it flagged?): Yes

Start and End Dates: 3/15/18 - 2/28/21

Restricted Research: YES

Academic Discipline: Department of Chemistry and Biochemistry

Department, Center, School, or Institute: College of Science

Title of Contract, Award, or Gift: Histone methylase MLL2 in regulation of SR-BI expression and plasma cholesterol

Name of Granting or Contracting Agency/Entity: National Institutes of Health (NIH)
CFDA Link: HHS
93.837

Program Title: N/A
CFDA Linked: Heart and Vascular Diseases Research

Note:

Cardiovascular disease (CVD) is the leading cause of death in both men and women worldwide. Malfunction in lipoprotein metabolism and elevated levels of plasma cholesterol are known causes of CVD and about half of all Americans are likely to have at least one of these risk factors. Individual characteristics that present additional risk factors for CVD include, gender and other factors which affect an individual’s internal hormonal milieu; age; diet; and genetic factors. Lipoprotein metabolism and cholesterol homeostasis are strongly regulated by low-density lipoprotein receptor (LDLR) and high-density lipoprotein receptor scavenger receptor type BI (SR-BI). Briefly, LDLR binds to plasma LDL and delivers LDL-cholesterol to peripheral tissues. In the liver, SR-BI, functions as a receptor for the cholesterol-rich HDL and serves to facilitate the selective delivery of HDL-cholesterol to the liver. Because SR-BI is critical in the regulation of plasma cholesterol levels, a complete understanding the mechanisms of SR-BI gene regulation and subsequent lipoprotein metabolism is necessary in order to develop effective therapies for CVD. Our preliminary studies demonstrate that SR-BI expression is induced, both in vitro and in vivo, by the ovarian hormone, 17?-estradiol (E2). We also show that the Mixed Lineage Leukemia (MLL) family of histone methylases coordinate with estrogen receptors (ER) to regulate E2-induced SR-BI expression [24]. Moreover, knockdown of MLL2 decreases hepatic SR-BI expression and subsequently elevates plasma cholesterol level in male mice, while E2-treatment to ovariectomized (OVX) animals induces hepatic SR-BI expression. Here, we propose to further elucidate the detailed molecular/epigenetic mechanisms by which E2 regulates SR-B1 expression and resultant hepatic function in vitro and in vivo. We have two specific aims. In the aim 1, we will: a) Analyze differential activation of ER subtypes and roles of MLL2 in E2 treated HepG2 cells overexpressing ER? or ER?, or in primary hepatocytes; b) Analyze the contribution of MLL2-histone methylation activity in SR-BI expression; c) Explore potential involvement of membrane ERs in SR-BI gene regulation; In the aim 2, We will investigate: a) Functionally characterize the effect of MLL2 on hepatic function and cholesterol regulation in vitro; and b) Study the roles ofMLL2 regulates in SR-BI expression, and consequent hepatic function, in female mice in an E2-dependent manner in vivo. . We will measure hepatic SR-BI expression and plasma HDL, LDL, and cholesterol in OVX E2-treated mice subjected to systemic MLL2 knockdown via AAV-shRNA. The proposed studies will reveal a novel epigenetic mechanism of E2-induced SR-BI gene expression and cholesterol homeostasis. Results from this work will have major implications regarding lipoprotein metabolism and cholesterol levels which, in turn, will update how we think about individual risk factors for CVD. Moreover, knowledge of E2 regulation of the mechanisms that affect hepatic function will inform decisions associated with CVD as well as discoveries of treatment and prevention customization. In addition to addressing an important scientific problem, this proposal will also serve to enrich student research experiences at UTA – a minority serving institution. The experiments outlined will provide students with meaningful and high quality training opportunities. The end result will ultimately enhance the research training environment at UTA, and increase the prospects for our students to pursue future careers in health-related fields.

Discussion: No discussion notes

 

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