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Characterization of age-related changes in spermatogonial dedifferentiation

Award Number: R21AG068103
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Characterization of age-related changes in spermatogonial dedifferentiation - Project Summary The broad, long-term objectives of this application are to characterize how age-related intrinsic changes in gene expression and age-related extrinsic changes in the niche microenvironment impact the process of dedifferentiation. This proposal will examine these issues using spermatogonial dedifferentiation - in which differentiating germ cells revert to become spermatogonial stem cells - in the Drosophila testis. State of the art techniques will be used to detect genome-wide binding of RNA Polymerase II in dedifferentiating spermatogonia. The proposal will capitalize upon the powerful genetics and lineage tracing available in Drosophila, as well as the ability to unequivocally identify the niche, spermatogonial stem cells, spermatogonia and somatic support cells in the Drosophila testis. This proposal is supported by published results demonstrating that spermatogonial dedifferentiation is required to maintain a robust pool of spermatogonial stem cells over a lifetime and that this process requires Jun N-terminal kinase (JNK) signaling. This work is also supported by unpublished preliminary data showing that the rate of spermatogonial dedifferentiation declines steeply during aging. Additionally, this proposal is supported by unpublished results showing that the niche microenvironment changes substantially during aging: in old males, an ectopic extracellular matrix accumulates around the niche. In the first aim, targeted DamID will be used to obtain the genome-wide binding of RNA Pol II only in reverting spermatogonia in testes from young and old males. Analyses of these data sets will reveal genes that are activated in young but not old spermatogonia. In the second aim, one or two validated genes from Aim 1 will be used to test the model that candidate gene depletion in young testes should decrease dedifferentiation rates and its overexpression should increase reversion rates in old males. Experiments in the second aim will also test the hypothesis that decreased dedifferentiation in old males is a result of reverting cells not upregulating extracellular matrix-binding proteins. The studies in this proposal will increase the knowledge base about how aging affects dedifferentiation in more complex system and will foster new avenues of research into mechanisms and treatments for age-related 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: 2024 ( Subtotal = $0 )
2024	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	4/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $211,875 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	12/30/2021	NON-COMPETING CONTINUATION	$190,687
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$21,188
														Subtotal = $211,875

Issue Date FY: 2021 ( Subtotal = $254,250 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	1	3/31/2021	NEW	$254,250
														Subtotal = $254,250

Grand Total All Awards = $466,125

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Characterization of age-related changes in spermatogonial dedifferentiation

Award Number: R21AG068103

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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