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The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia

Award Number: R01HL157118
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia - The role of GSK3/PPAR-δ/FAO/mitophagy pathway in regulating hematopoietic stem cell homeostasis and function Abstract Hematopoietic stem cells (HSCs) possess the abilities to both produce stem cells, a property known as self-renewal, and give rise to all differentiated hematopoietic lineages. Clinically, HSCs are therapeutically valuable for transplantation in treatment of various hematologic malignances. Despite remarkable progress made in the research of HSCs during the past three decades, the molecular mechanisms regulating HSC homeostasis and function are still not fully understood. Our previous published showed that GSK3 plays an essential role in regulating HSC homeostasis. Specifically, knockdown of Gsk3 promote transient expansion and long-term exhaustion of HSC in vivo. Our new preliminary studies demonstrated that GSK3 functions through PPAR-δ/FAO/mitophagy pathway to regulate HSC division symmetry; inhibition of GSK3 induces mitophagy and conversely, blocking PPAR-δ/FAO/mitophagy can reverse the enhanced self-renewal phenotype that is associated with GSK3 inhibition. In this study, we will first examine how GSK3 regulates PPAR-δ, which in turn regulates mitophagy and HSC division symmetry. Secondly, we will investigate whether loss-of- function of Ppar-δ, Park2 or Pink1 (two mitophagy key regulators) reverse the functional defect of Gsk3b-deficient HSC in vivo. Lastly, we will explore whether GSK3 controls FAO and lipid metabolism to regulate HSC function and homeostasis. Our study will provide significant new insights into the molecular mechanisms underlying GSK3-dependent regulation of HSC homeostasis and function. The knowledge learned may facilitate bone marrow transplantation for treating diverse hematological diseases.


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: 2025 ( Subtotal = $448,906 )
2025	2025	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	000	4	12/16/2024	NON-COMPETING CONTINUATION	$448,906
														Subtotal = $448,906

Issue Date FY: 2024 ( Subtotal = $488,809 )
2024	2024	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	001	3	6/12/2024	NON-COMPETING CONTINUATION	$39,903
2024	2024	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	000	3	1/4/2024	NON-COMPETING CONTINUATION	$448,906
														Subtotal = $488,809

Issue Date FY: 2023 ( Subtotal = $511,939 )
2023	2023	CORIELL INSTITUTE FOR MEDICAL RESEARCH INC	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	000	2	12/27/2022	NON-COMPETING CONTINUATION	$460,745
2023	2023	CORIELL INSTITUTE FOR MEDICAL RESEARCH INC	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	001	2	3/10/2023	NON-COMPETING CONTINUATION	$51,194
														Subtotal = $511,939

Issue Date FY: 2022 ( Subtotal = $524,381 )
2022	2022	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	001	1	1/14/2022	NEW	$0
2022	2022	CORIELL INSTITUTE FOR MEDICAL RESEARCH, INC.	403 HADDON AVE	CAMDEN	NJ	08103	CAMDEN	USA	Blood Diseases and Resources Research	000	1	12/31/2021	NEW	$524,381
														Subtotal = $524,381

Grand Total All Awards = $1,974,035

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The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia

Award Number: R01HL157118

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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