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Mediators for dynamic regulation of Star transcription in Leydig cells

Leydig 细胞中 Star 转录动态调节的介质

基本信息

批准号：
9924272
负责人：
COLIN ROBERT JEFCOATE
金额：
$ 56.25万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-16 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924272
关键词：
Acute Adult Age Androgens Animals Biology Cell Differentiation process Cell physiology Cells Cholesterol Chromatin Clinical Congenital Abnormality Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Diagnosis Disease Endocrine Endocrine Disruptors Endocrine disruption Environment Enzymes Erinaceidae Event Excision Exposure to Fatigue Fetal Development Fluorescent in Situ Hybridization Gatekeeping Gene Expression Regulation Genes Genetic Diseases Genetic Transcription Genitourinary system Health Image In Vitro Individual Infertility Kinetics Knowledge Learning Life Maintenance Mediator of activation protein Messenger RNA Microfluidics Molecular Newborn Infant Output Paracrine Communication Pathway interactions Pattern Physiologic pulse Physiological Play Population Pregnancy Production Prostate Puberty Publishing RNA RNA Splicing Regulation Reporting Resolution Role Series Sex Differentiation Disorders Signal Transduction Sleep Apnea Syndromes Source Steroids Stimulus Swelling Syndrome Techniques Technology Testing Testis Testosterone Time Trans-Activators Transcript Transcriptional Regulation arm bone loss bone mass cholesterol control design experimental study fetal genetic regulatory protein in vivo innovation leydig interstitial cell male men molecular imaging mouse model muscle form novel paracrine prevent public health relevance response sertoli cell sex development disorder subfertility testosterone replacement therapy tool trend

项目摘要

7. Project summary/Abstract Leydig cells within the testis are the source of androgens that promote virility at both fetal and adult stages, but Leydig cell populations are distinct at each age. As such, adult and fetal Leydig cells function to synthesize testosterone in distinct cellular and endocrine environments. The AIMs of this proposal are focused on regulation of Star, the known gatekeeper in controlling access of cholesterol to enzymatic activity of the series of steroidogenic enzymes required for conversion to testosterone. Here we focus on novel regulatory events that exert dynamic interactions with Star chromosomal loci that will explain how fluctuating Star transcript accumulation can relate to changes in androgen synthesis. Previously, we used high-resolution fluorescent in situ hybridization (HR-FISH) to localize and quantify a unique pattern for primary, spliced, and mRNA species accumulation for Star compared to other steroidogenic genes within single Leydig cells. We will use this and other innovative techniques to compare results from studies that investigate individual adult and fetal Leydig cells in vitro, within MA10 cells and primary cultures, and in vivo, within whole testes. Pulsatile LH stimulates primarily cAMP/PKA signals to promote testosterone synthesis in adult Leydig cells. While we have substantial means to explain how Star transcription is turned ON by LH/PKA, we understand little about what happens when the pulse is removed, and even less about the interpulse interval. In AIM 1, we will test the hypothesis that the events occurring at Star loci during this interval are just as critical to controlling testosterone output as the initial stimulus. Meanwhile, the external stimuli that maintain androgen synthesis in fetal Leydig cells are less clear, but evidence points to paracrine signals, with PKA activity playing a role. Another paracrine factor, Sertoli cell-derived Desert Hedgehog (Hh) is known to initiate fetal Leydig cell differentiation, but its role in their maintenance has not been tested. Once differentiated, fetal Leydig cells produce androgens at a steadily increasing rate until late gestation. Therefore, in AIM 2, we will test the hypothesis that regulatory events on Star loci facilitate a controlled increase in androgens within the fetal Leydig cell that compare to those that occur during the interpulse interval in adult Leydig cells. Our findings have the potential to explain fundamental biology underlying steroidogenic control and will have a profound impact on our ability to explore mechanisms by which disturbances in testosterone synthesis, as in endocrine disruption, cause significant clinical ramifications in males from all stages of life.

7. 项目总结/文摘