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Defining the signaling pathways that direct adult tissue stem cells to exit multipotency

Award Number: R01GM124491
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/23/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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Defining the signaling pathways that direct adult tissue stem cells to exit multipotency - Adult stem cells can give rise to entire tissues and this regenerative ability is essential both for repairing tissues after injury, and for maintaining tissues throughout life. Given their important role in normal biology, aging, and disease, there is significant interest in defining the signaling networks that direct stem cell fate. While prior research has identified key regulators of mammary stem/progenitor cell biology, many regulators have yet to be identified, and how these various regulators function within signaling and transcriptional networks to modulate mammary stem/progenitor fate remains poorly understood. Our long-term goal is to define how the internal circuitry of stem/progenitor cells integrates external signals to regulate their fate. We study mammary tissue because of its unique advantages as an experimental model, and because this tissue undergoes multiple cycles of expansion and regression throughout life -- exemplifying the importance of stem cells in adult tissues. This study will contribute essential new knowledge of the signaling networks that regulate stem cell biology by defining a new link between two known regulators of stem cell fate (RUNX1, NOTCH), and by identifying a novel kinase (DDR1) that was previously not known to regulate mammary stem cell fate. The specific objectives of this project are to define how two key regulators, RUNX1 and NOTCH, cooperate to drive the lineage specification of mammary stem/progenitor cells (Aim 1), and to establish how a novel regulator, DDR1, promotes the differentiation of mammary stem and progenitor cells (Aim 2). We will address these objectives with two specific aims: (1) Define the RUNX1- and NOTCH-regulated transcriptional network that drives mammary stem/progenitor differentiation. (2) Define the signaling network activated by DDR1 to regulate stem/progenitor cell differentiation. This study will contribute public health by identifying new genes and signaling networks that regulate stem cell fate in adult tissues, which will facilitate the development of new therapies that harness the power of stem cells for regenerative medicine. This study is experimentally innovative in how it leverages our recently developed hydrogel cultures for growing patient-derived mammary tissues, in synergistic combination with cutting edge genomic approaches – including CRISPR and single-cell profiling – to dissect the transcriptional networks and signaling cascades that regulate stem/progenitor fate in human mammary tissue. In summary, these investigations will contribute to our fundamental understanding of how adult stem cell differentiation is genetically controlled, and will yield important knowledge that will be necessary to fully harness the power of adult stem cells for regenerative medicines.


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	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Biomedical Research and Research Training	000	5	4/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $419,321 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Biomedical Research and Research Training	000	5	7/15/2022	NON-COMPETING CONTINUATION	$412,500
2022	2018	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	001	1	9/26/2022	NEW	$6,821
														Subtotal = $419,321

Issue Date FY: 2021 ( Subtotal = $412,500 )
2021	2021	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Biomedical Research and Research Training	000	4	7/22/2021	NON-COMPETING CONTINUATION	$412,500
														Subtotal = $412,500

Issue Date FY: 2020 ( Subtotal = $412,500 )
2020	2020	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Biomedical Research and Research Training	002	3	7/28/2020	NON-COMPETING CONTINUATION	$412,500
2020	2019	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Biomedical Research and Research Training	001	2	1/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$323,335
2020	2018	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	1/13/2020	NEW	-$323,335
														Subtotal = $412,500

Issue Date FY: 2019 ( Subtotal = $412,500 )
2019	2019	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Biomedical Research and Research Training	001	2	9/17/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$412,500
2019	2018	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	9/16/2019	NEW	$0
														Subtotal = $412,500

Issue Date FY: 2018 ( Subtotal = $487,500 )
2018	2018	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	8/23/2018	NEW	$487,500
														Subtotal = $487,500

Grand Total All Awards = $2,144,321

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Defining the signaling pathways that direct adult tissue stem cells to exit multipotency

Award Number: R01GM124491

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/23/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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