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Combinatorial signal integration in the maintenance and renewal of adult germline stem cell fate

Award Number: K99GM154143
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Combinatorial signal integration in the maintenance and renewal of adult germline stem cell fate - Project Summary/Abstract Throughout an organism’s lifetime, adult stem cells (aSCs) play a pivotal role in maintaining tissue homeostasis. aSCs possess the remarkable ability to undergo asymmetric divisions, simultaneously renewing themselves and producing differentiating daughter cells. Unlike aSCs, those daughter cells lack the capacity for self-renewal and instead undergo terminal differentiation. Such divergent cell behaviors – asymmetric division and self-renewal by aSCs versus symmetric division and differentiation by their daughters – suggest that aSCs and their daughters are fundamentally distinct cell types. However, contrary to this model, daughter cells can dedifferentiate to fully regain aSC identity, including a return to stem cell potency. Indeed, dedifferentiation is frequently required to reestablish aSC populations after loss. These phenomena present a fundamental paradox: how can stem cells and their differentiating progeny maintain different behaviors, yet preserve the same potential? Notably, both these exclusively properties are clearly present in germline stem cell (GSC) populations, and are strictly required to maintain species integrity. Drosophila male GSCs are an exceptionally tractable model of aSC biology. In preliminary studies with this model, I discovered that combinatorial integration of two independent signaling factors enables cells to achieve distinct behaviors while maintaining equivalent potency. I refer to this concept as “two-factor authentication,” analogizing stem cell maintenance to cybersecurity. Building on these preliminary discoveries, this proposal aims to comprehensively characterize how adult stem cell systems balance regenerative plasticity with the maintenance of discrete cell behaviors. In Aim 1, I will determine how combinatorial signals from the stem cell niche yield distinct cellular states, including self-renewal, differentiation, and dedifferentiation. In Aim 2, I will determine if GSCs asymmetrically retain a stemness signature that maintains their unique features. Finally, in Aim 3, I will examine the factors involved in reestablishment of GSC fate during dedifferentiation in multiple contexts. Expanding my prior expertise in organismal stem cell biology with advanced bioinformatic and genetic tools will enable the completion of each of these aims. Together, these experiments defining GSC regulation (Aim 1), identity (Aim 2), and regeneration (Aim 3) will allow for a comprehensive assessment of the core requirements to set and maintain these exceptional stem cells.


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: 2026 ( Subtotal = $162,800 )
2026	2026	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	1/16/2026	NON-COMPETING CONTINUATION	$162,800
														Subtotal = $162,800

Issue Date FY: 2025 ( Subtotal = $162,800 )
2025	2025	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	001	1	7/31/2025	SUPPLEMENT FOR EXPANSION	$37,800
2025	2025	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	12/16/2024	NEW	$125,000
														Subtotal = $162,800

Grand Total All Awards = $325,600

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Combinatorial signal integration in the maintenance and renewal of adult germline stem cell fate

Award Number: K99GM154143

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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