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Transfer of grant 5R01HD040793 - Intercellular networks and luminal acidification in the male reproductive tract

Award Number: R01HD040793
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/ABSTRACT Spermatozoa acquire their ability to fertilize an oocyte as they transit through the epididymis. The luminal fluid of the epididymal duct is acidic and has a low bicarbonate (HCO3-) concentration: both factors are important for keeping sperm quiescent during their maturation and storage. In the previous funding periods, we showed that several population of epithelial cells that line the epididymal lumen work in a concerted manner to regulate luminal pH. Clear cells (CCs) acidify the lumen via the vacuolar proton pump V-ATPase located in their apical membrane. During sexual arousal, stimulated principal cells (PCs) secrete HCO3- into the lumen, which contributes to luminal alkalinization, a process that primes sperm before ejaculation. We showed that, in addition to HCO3-, PCs also secrete adenosine triphosphate (ATP) into the lumen. Male infertility is associated with a defect in purinergic regulation by ATP and its hydrolysis product adenosine. Our previous data revealed that PCs and CCs engage in crosstalk that relies not only on HCO3-, but also on ATP and adenosine, which then act as extracellular mediators that activate H+ secretion by CCs to restore luminal pH to its resting acidic condition. Importantly, we also found that in the steady state, PCs contribute to luminal acidification via the Na+/H+ exchanger NHE3. PCs can, therefore, switch from being acid-secretors to base-secretors in response to physiological cues. Aim 1 will characterize this dual pH-regulating function of PCs by answering the question: how do PCs switch from being H+-secreting to HCO3--secreting cells? We will examine the role of circulating agonists in this switch between H+ secretion and HCO3- secretion by PCs. We will also characterize ATP secretion by PCs, and its hydrolysis via extracellular ectonucleotidases to produce adenosine. Aim 2 will define the PC-CC crosstalk that regulates H+ secretion by CCs. We will dissect the purinergic regulation of V-ATPase- dependent H secretion by CCs. We will use two-photon intravital microscopy to characterize the role of HCO3- + , ATP and adenosine as extracellular mediators that are secreted from PCs to regulate V-ATPase-dependent H+ secretion in CCs. Our proposed multidisciplinary approach involves a battery of complementary and innovative in vivo and in vitro procedures. These studies will provide new insights into the regulation of luminal acidification in the epididymis, and will dissect intercellular communication pathways that are essential for the establishment of male fertility. Ultimately, a better understanding of basic mechanisms involved in sperm maturation in the post-testicular male reproductive tract will drive clinical advances for the treatment of male infertility.


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 = $0 )
2023	2021	UNIVERSITE LAVAL	2345 ALLEE DES BIBLIOTHEQUES	QUEBEC	QC			CAN	Child Health and Human Development Extramural Research	000	18	2/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $1,047 )
2022	2019	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	16	9/26/2022	NON-COMPETING CONTINUATION	$1,047
														Subtotal = $1,047

Issue Date FY: 2021 ( Subtotal = $217,335 )
2021	2021	UNIVERSITE LAVAL	2345 ALLE DES BIBLIOTHEQUES	QUEBEC	QC			CAN	Child Health and Human Development Extramural Research	000	18	7/30/2021	NON-COMPETING CONTINUATION	$217,335
														Subtotal = $217,335

Issue Date FY: 2020 ( Subtotal = $221,770 )
2020	2020	UNIVERSITE LAVAL	2345 ALLE DES BIBLIOTHEQUES	QUEBEC	QC	G1V 0A6		CAN	Child Health and Human Development Extramural Research	001	17	5/4/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$221,770
2020	2020	UNIVERSITE LAVAL	2345 ALLE DES BIBLIOTHEQUES	QUEBEC	QC	G1V 0A6		CAN	Child Health and Human Development Extramural Research	004	17	9/25/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,457
2020	2020	UNIVERSITE LAVAL	2345 ALLE DES BIBLIOTHEQUES	QUEBEC	QC	G1V 0A6		CAN	Child Health and Human Development Extramural Research	002	17	5/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	003	16	9/25/2020	NON-COMPETING CONTINUATION	-$87,457
2020	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	16	5/4/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $221,770

Issue Date FY: 2019 ( Subtotal = $347,753 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	16	4/2/2019	NON-COMPETING CONTINUATION	$347,753
														Subtotal = $347,753

Issue Date FY: 2018 ( Subtotal = $347,753 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	15	4/18/2018	NON-COMPETING CONTINUATION	$347,753
														Subtotal = $347,753

Issue Date FY: 2017 ( Subtotal = $347,753 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	14	7/11/2017	COMPETING CONTINUATION	$347,753
2017	2015	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	13	5/23/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $347,753

Issue Date FY: 2015 ( Subtotal = $414,182 )
2015	2015	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	13	2/17/2015	NON-COMPETING CONTINUATION	$414,182
														Subtotal = $414,182

Issue Date FY: 2014 ( Subtotal = $400,880 )
2014	2014	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	12	2/21/2014	NON-COMPETING CONTINUATION	$400,880
														Subtotal = $400,880

Issue Date FY: 2013 ( Subtotal = $379,995 )
2013	2013	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	11	3/13/2013	NON-COMPETING CONTINUATION	$360,375
2013	2013	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	001	11	5/20/2013	NON-COMPETING CONTINUATION	$19,620
														Subtotal = $379,995

Issue Date FY: 2012 ( Subtotal = $388,751 )
2012	2012	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	10	3/19/2012	NON-COMPETING CONTINUATION	$388,751
														Subtotal = $388,751

Issue Date FY: 2011 ( Subtotal = $383,175 )
2011	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	9	4/12/2011	COMPETING CONTINUATION	$383,175
														Subtotal = $383,175

Issue Date FY: 2009 ( Subtotal = $313,020 )
2009	2009	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	8	6/2/2009	NON-COMPETING CONTINUATION	$313,020
														Subtotal = $313,020

Issue Date FY: 2008 ( Subtotal = $313,020 )
2008	2008	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	7	5/22/2008	NON-COMPETING CONTINUATION	$313,020
														Subtotal = $313,020

Issue Date FY: 2007 ( Subtotal = $319,408 )
2007	2007	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	6	5/18/2007	NON-COMPETING CONTINUATION	$319,408
														Subtotal = $319,408

Issue Date FY: 2006 ( Subtotal = $328,947 )
2006	2006	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	5	5/24/2006	NON-COMPETING CONTINUATION	$328,947
														Subtotal = $328,947

Issue Date FY: 2005 ( Subtotal = $336,863 )
2005	2005	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Child Health and Human Development Extramural Research	000	4	8/3/2005	COMPETING CONTINUATION	$336,863
														Subtotal = $336,863

Issue Date FY: 2003 ( Subtotal = $494,568 )
2003	2003	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Population Research	000	3		NON-COMPETING CONTINUATION	$494,568
														Subtotal = $494,568

Issue Date FY: 2002 ( Subtotal = $494,568 )
2002	2002	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Population Research	000	2	3/30/2002	NON-COMPETING CONTINUATION	$494,568
														Subtotal = $494,568

Issue Date FY: 2001 ( Subtotal = $512,318 )
2001	2001	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Population Research	000	1	9/19/2001	NEW	$512,318
														Subtotal = $512,318

Grand Total All Awards = $6,563,106

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Transfer of grant 5R01HD040793 - Intercellular networks and luminal acidification in the male reproductive tract

Award Number: R01HD040793

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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