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Mechanisms of TGFb in prostaglandin metabolism and fertilization

Award Number: F30HD094446
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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Mechanisms of TGFb in prostaglandin metabolism and fertilization - PROJECT SUMMARY Infertility is a growing problem that affects millions of people in Western countries. An important reproductive process that is understudied in internally fertilizing animals is the process by which sperm find the oocyte. Increasing evidence suggest that sperm respond to chemotactic cues within the oviduct to locate recently ovulated oocytes. Prostaglandins (PGs) are fat-derived signaling molecules that are implicated in sperm chemotaxis and other reproductive processes. The TGFβ superfamily of peptide ligands is critical for human ovarian follicle development and fertilization, but the underlying mechanisms are not well understood. In the nematode C. elegans, the TGFβ ligand DAF-7 couples environmental conditions to female fertility through the modulation of F-series prostaglandin (CePGF) metabolism in the ovary. Oocytes secrete a mixture of CePGF isomers that function as sperm chemoattractants. CePGFs are synthesized by a novel, TGFβ dependent mechanism that may be conserved in mammals. The objective of this project is to investigate the mechanism by which DAF-7/TGFβ regulates CePGF levels and sperm chemotaxis. Preliminary data demonstrate that the DAF-3 co-SMAD transcription factor represses CePGF synthesis or enhances CePGF breakdown. The central hypothesis is that DAF-3 acts in transcriptionally active oocyte precursors to regulate expression of genes critical for CePGF metabolism. Two independent aims are proposed to test this hypothesis. AIM 1 will identify cellular and subcellular sites of DAF-3 action to promote sperm guidance. CRISPR/Cas9 technology will be used to determine endogenous DAF-3 expression. Transgenic approaches will be used to identify the key cell types in which DAF-3 function is necessary and sufficient to regulate sperm chemotaxis. AIM 2 will identify direct or indirect DAF-3 transcriptional targets that are critical for sperm guidance and CePGF metabolism. Preliminary data using RNA sequencing and RNA-mediated interference suggest that multiple DAF-3 target genes act in the germ line to regulate CePGF metabolism. Genetic and mass spectrometry approaches will be used to test this model. The results obtained from this project will provide novel insight into the mechanism(s) by which TGFβ signaling regulates female fertility, as well as the function(s) and regulation of a new class of PGs found in C. elegans and mammals.


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 = $215 )
2023	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	000	4	12/29/2022	NON-COMPETING CONTINUATION	$215
														Subtotal = $215

Issue Date FY: 2021 ( Subtotal = $11,661 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	001	4	8/10/2021	NON-COMPETING CONTINUATION	-$34,442
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	000	4	2/18/2021	NON-COMPETING CONTINUATION	$46,103
														Subtotal = $11,661

Issue Date FY: 2020 ( Subtotal = $45,587 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	000	3	3/3/2020	NON-COMPETING CONTINUATION	$45,587
														Subtotal = $45,587

Issue Date FY: 2019 ( Subtotal = $37,692 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	001	2	3/19/2019	NON-COMPETING CONTINUATION	$0
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	000	2	1/29/2019	NON-COMPETING CONTINUATION	$37,692
														Subtotal = $37,692

Issue Date FY: 2018 ( Subtotal = $37,200 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	000	1	2/26/2018	NEW	$36,720
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Child Health and Human Development Extramural Research	001	1	5/23/2018	NEW	$480
														Subtotal = $37,200

Grand Total All Awards = $132,355

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Mechanisms of TGFb in prostaglandin metabolism and fertilization

Award Number: F30HD094446

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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