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Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP

Award Number: K01DK129409
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 04/02/2025

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Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP - Project Summary/Abstract Hematopoietic stem cells (HSCs) are capable of producing all erythroid, myeloid and lymphoid blood cells of an organism. Coupled with their unique capacity for self-renewal, successful transplantation of healthy HSCs is the only therapy currently available that can completely replace and restore the blood system in patients with leukemia and lymphoma. Despite this need, HSCs presently cannot be efficiently created or cultured in vitro, suggesting that extrinsic factors supporting their growth and development in vivo are lacking from existing protocols. Previous work from our lab demonstrated that blood flow is an essential non-genetic environmental cue required for HSC production in vertebrate embryos, mediated in part by stimulating mechanical activation of the Yes-associated protein (YAP) transcription factor (TF). This proposal intends to resolve the physical, genetic and molecular mechanisms underlying mechanically-activated, YAP-driven HSC production. YAP, while a potent co-activator of gene expression, lacks DNA-binding ability of its own. To understand the molecular logic behind flow/YAP-driven hematopoiesis, the goal of the first aim is to employ chemical, physical and genetic perturbation of shear stress and cyclic stretch in live zebrafish embryos to assess the impact of these individual components of hemodynamic force on HSC production from hemogenic endothelium (HE). To this will be added tissue- specific transcriptomic and genome-wide YAP/DNA interaction profiling from sorted HE from wildtype zebrafish, flow-deficient and yap-/- animals (with normal blood flow) in order to discriminate flow-dependent gene regulatory modules and transcriptional targets that rely on YAP. Hypothesis-driven candidate TFs will be tested in vivo and in vitro to evaluate YAP-interaction ability and uncover key partners required for normal YAP-dependent hematopoiesis. In the second aim, the zebrafish system will be used to investigate candidate membrane- localized proteins, Piezos and Integrins, as components linking hemodynamic forces with YAP activation. These studies stand to provide a comprehensive “membrane-to-nucleus” paradigm for how blood flow activates YAP to guide developmental hematopoiesis, which may improve current efforts to generate or expand HSCs. As a postdoctoral fellow, Dr. Sugden will conduct his research in the laboratory of Dr. Trista North at Boston Children's Hospital. Her expertise in extrinsic regulation of developmental hematopoiesis, together with dedicated co-mentorship by Dr. George Daley (an expert in stem cell biology and hematology) and a strong advisory team provide an exceptionally well-supported environment for career development and research training. Dr. Sugden will build on a solid background in developmental genetics and live-imaging, by adding new technologies in transcription factor/DNA interaction profiling, transcriptomics and in vitro methods to study protein interactions. A rigorous research and training plan lay the groundwork for success, both in the mentored and independent phases of the award. The environment at Boston Children's Hospital and Harvard Medical School will provide the ideal surroundings to support Dr. Sugden to become a successful independent scientist.


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 = $0 )
2026	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $153,046 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/28/2025	NON-COMPETING CONTINUATION	$153,046
														Subtotal = $153,046

Issue Date FY: 2024 ( Subtotal = $153,046 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/25/2024	NON-COMPETING CONTINUATION	$153,046
														Subtotal = $153,046

Issue Date FY: 2023 ( Subtotal = $152,246 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/28/2023	NON-COMPETING CONTINUATION	$152,246
														Subtotal = $152,246

Issue Date FY: 2022 ( Subtotal = $153,846 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/24/2022	NON-COMPETING CONTINUATION	$153,846
														Subtotal = $153,846

Issue Date FY: 2021 ( Subtotal = $155,346 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/9/2021	NEW	$155,346
														Subtotal = $155,346

Grand Total All Awards = $767,530

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Mechanisms of Flow-driven Transcriptional Control of Hematopoietic Stem Cell Development by YAP

Award Number: K01DK129409

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 04/02/2025

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