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Transcriptional networks coordinating luminal environment in the human epididymis: the role of the androgen receptor.

Award Number: R01HD068901
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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SUMMARY: Androgens are steroid hormones with a pivotal role in determining male characteristics, which bind to the androgen receptor (AR) to direct a unique transcriptional program. Although best studied in the human prostate and in prostate cancer, the AR transcriptional network also controls normal functions of other male reproductive tract tissues, including the epididymis and the vas deferens. A critical function of the epididymis, the proximal part of the male genital ducts that transport testicular products out of the body, is in sperm maturation. Immature sperm leaving the testis acquire the capacity to fertilize an egg during their passage through the head and body of the epididymis. Many factors contribute to establishing and maintaining the specific epididymis luminal environment that is required for normal sperm maturation. These include hormones and other testicular products that enter the duct, though the epithelium lining the epididymis has a pivotal role. The proximal luminal fluid has a low pH and bicarbonate concentration to preserve sperm motility and relatively high potassium concentrations to facilitate sperm quiescence. Multiple ion channels, ion exchangers, transporters and water channels in the apical or basolateral membranes of the epididymis epithelium participate in fine-tuning the luminal fluid. Building upon a) substantial preliminary data on the AR transcriptional network in human epididymis epithelial (HEE) cells, which suggest novel co-factors for this TF are involved in the epididymis, together with b) an innovative HEE organoid model, our goal is to test the overarching hypothesis that the Androgen Receptor is pivotal to establishing and maintaining normal functions of the human epididymis epithelium. Moreover, that through the recruitment of specific co-factors, AR orchestrates a unique transcriptional program in this tissue. In the first specific aim we will determine the mechanisms through which androgens impact the differentiation and function of the human epididymis epithelium. We will use a novel epididymis organoid model for functional studies together with single cell RNA- sequencing (scRNA-seq). These experiments will provide novel and important insights into the role of androgens in the biology of the human epididymis epithelium and the transcriptional network that coordinates its functions. Studies in the second aim will determine the mechanisms of interaction of AR with other co- factors including RUNX1 and CEBPß and how these factors integrate into the transcriptional network in the human epididymis epithelium. We will also investigate the hierarchy of dependency of AR, RUNX1 and CEBPß using genome wide and locus-specific assays. A gene of particular interest is the cystic fibrosis transmembrane conductance regulator (CFTR), which establishes and maintains chloride and bicarbonate gradients in the epididymis lumen. CFTR recruits a unique set of cis-regulatory elements in HEE cells, some of which also bind AR. These data may facilitate the identification of novel targets for male contraceptives and also have a profound impact on therapeutic approaches to restore male fertility in epididymis disease.


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 = $339,227 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	9	6/2/2023	NON-COMPETING CONTINUATION	$339,227


Issue Date FY: 2022 ( Subtotal = $339,227 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	8	5/2/2022	NON-COMPETING CONTINUATION	$339,227


Issue Date FY: 2021 ( Subtotal = $339,227 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	7	5/6/2021	NON-COMPETING CONTINUATION	$339,227


Issue Date FY: 2020 ( Subtotal = $345,792 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Child Health and Human Development Extramural Research	000	6	4/15/2020	COMPETING CONTINUATION	$345,792


Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Child Health and Human Development Extramural Research	000	5	12/6/2017	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2015 ( Subtotal = $286,650 )
2015	2015	ANN & ROBERT H. LURIE CHILDREN`S HOSPITAL OF CHICAGO	2300 CHILDRENS PLAZA	CHICAGO	IL	60614	COOK	USA	Child Health and Human Development Extramural Research	000	5	6/26/2015	NON-COMPETING CONTINUATION	$286,650


Issue Date FY: 2014 ( Subtotal = $285,768 )
2014	2014	ANN & ROBERT H. LURIE CHILDREN`S HOSPITAL OF CHICAGO	2300 CHILDRENS PLAZA	CHICAGO	IL	60614	COOK	USA	Child Health and Human Development Extramural Research	000	4	7/17/2014	NON-COMPETING CONTINUATION	$285,768


Issue Date FY: 2013 ( Subtotal = $279,006 )
2013	2013	ANN & ROBERT H. LURIE CHILDREN`S HOSPITAL OF CHICAGO	2300 CHILDRENS PLAZA	CHICAGO	IL	60614	COOK	USA	Child Health and Human Development Extramural Research	000	3	7/12/2013	NON-COMPETING CONTINUATION	$279,006


Issue Date FY: 2012 ( Subtotal = $294,000 )
2012	2012	ANN & ROBERT H. LURIE CHILDREN`S HOSPITAL OF CHICAGO	2300 CHILDRENS PLAZA	CHICAGO	IL	60614	COOK	USA	Child Health and Human Development Extramural Research	000	2	7/11/2012	NON-COMPETING CONTINUATION	$294,000


Issue Date FY: 2011 ( Subtotal = $294,000 )
2011	2011	ANN & ROBERT H. LURIE CHILDREN`S HOSPITAL OF CHICAGO	2300 CHILDRENS PLAZA	CHICAGO	IL	60614	COOK	USA	Child Health and Human Development Extramural Research	000	1	8/8/2011	NEW	$294,000


Grand Total All Awards = $2,802,897

Sum of Action Amount is $2,802,897;

Grand Total = $2,802,897

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Transcriptional networks coordinating luminal environment in the human epididymis: the role of the androgen receptor.

Award Number: R01HD068901

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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