Epigenetic control of spermatogonial stem cell self-renewal

Active Project Grant Awarded Last action

Award ID
R01HD109253
Recipient
Awarding agency
Obligated
$3,521,683

Award facts

Completion date 70% complete
Place of performance
Philadelphia, PA 19104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Males produce sperm continuously through adult life, driven by the renewal of spermatogonial stem cells (sscs). The long-term objective of this application is to determine the role of a novel epigenetic program that we have recently identified in regulating the renewal of adult sscs. Sscs can both self-renew and produce progenitor spermatogonia that will differentiate to initiate spermatogenesis. The balance between SSC self- renewal and differentiation is key for life-long production of sperm in adult males. Both SSC transplantation and in vitro SSC cultures have enabled functional studies of SSC and allowed for advancement of translational applications in animal transgenesis. However, while much is known about spermatogenesis, the regulation of SSC self-renewal remains poorly understood. Stem cell renewal requires both stem cell-intrinsic factors and external niche factors, only a handful of which have been identified (plzf, RB, NANOS2, gdnf, ETV5, etc.). Notably, their functions in SSC self-renewal have been revealed through genetic studies. Despite these advances, the molecular biological control of SSC remains poorly understood. We have identified an epigenetic factor DOT1L, the sole H3K79 methyltransferase, as a novel master regulator of mouse SSC self- renewal. Moreover, by chemically inhibiting DOT1L, we were able to identify specific target genes that likely contribute to SSC renewal. We propose an innovative multi-pronged (genetic, chemical, genomic, and proteomic) approach to comprehensively elucidate this novel epigenetic program in sscs. As failure in SSC self-renewal leads to a lack of sperm production and thus male infertility, completion of this project will lay a firm foundation for molecular dissection of SSC stem cell renewal and open new avenues of research in SSC biology and reproductive medicine.

Transactions

Action Obligated Date
Amendment $382,143
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Amendment $35,104
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Amendment $351,051
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Amendment $406,838
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Original award $406,838
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Subawards

Subrecipient Amount Awarded
The Kitasato Institute "Projects Main Goal The main goal is to perform the experiments as proposed in Subaim 2.1: Analysis of nine homeobox genes in SSCs by knockdown and… $45,441
The Kitasato Institute Projects Main Goal The main goal is to perform the experiments as proposed in Subaim 2.1: Analysis of nine homeobox genes in SSCs by knockdown and… $45,441
The Kitasato Institute $45,900

Quick answers

Who received award R01HD109253?

R01HD109253 was awarded to The Trustees Of The University Of Pennsylvania by National Institute of Child Health and Human Development (National Institutes of Health) on June 5, 2023.

How much is award R01HD109253 worth?

$3,521,683 has been obligated on R01HD109253.

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