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SHP2's Regulation of the Bone Marrow Stroma and Hematopoietic Crosstalk

Award Number: R01DK138630
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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SHP2's Regulation of the Bone Marrow Stroma and Hematopoietic Crosstalk - (PLEASE KEEP IN WORD, DO NOT PDF) (Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text.) It has been reported that depletion of RUNX21 or LepR2 in mesenchymal stem/progenitor cells (MSPCs) reduces bone mass and increases bone marrow (BM) adipocytes (BMA), and that PDGFRβ activation drives MSPC expansion and BM vasculogenesis, finally influencing hematopoiesis3. Our preliminary data show that mice lacking SHP2 in the Osterix+ stromal progenitor cells (O+SPCs) have similarly increased BMA and BM vasculature and skewed lymphopoiesis. We have not yet determined the molecular mechanism(s) by which SHP2 exerts its influence on O+SPCs and hematopoietic cells. However, the phenotypic similarity of mice lacking SHP2, RUNX2, LepR, or PDGFR in O+SPCs leads us to hypothesize that SHP2 influences the osteogenic, adipogenic and/or stromogenic fate of O+SPCs by modifying the transcription activity of RUNX2 and the kinase activity of PDGFR, and that altered BM O+SPCs change the cellular and molecular constituents of the BM niche and subsequently hematopoiesis. To test this novel hypothesis, we will complete two specific aims. In Aim 1 we will interrogate the impact of SHP2 depletion on RUNX2 transcriptional activity in O+SPCs, while in Aim 2 we will determine the effect of SHP2 depletion on stromogenic differentiation of O+SPCs and hematopoisis in vitro and in vivo. O+SPCs participate in BM hematopoietic niche construction and maintenance, and both SHP2 and RUNX2 influence O+SPCs. This innovative study will yield foundational information regarding SHP2’s regulatory role in O+SPCs and its consequent role in hematopoiesis and BM vasculogenesis. This information will significantly advance our understanding of the effect and importance of crosstalk between BM stromal cells and hematopoietic cells, and hematopoietic malignancy.


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 = $493,310 )
2026	2026	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/26/2026	NON-COMPETING CONTINUATION	$493,310
														Subtotal = $493,310

Issue Date FY: 2025 ( Subtotal = $493,310 )
2025	2025	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/23/2025	NON-COMPETING CONTINUATION	$493,310
														Subtotal = $493,310

Issue Date FY: 2024 ( Subtotal = $493,310 )
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/13/2024	NEW	$493,310
														Subtotal = $493,310

Grand Total All Awards = $1,479,930

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SHP2's Regulation of the Bone Marrow Stroma and Hematopoietic Crosstalk

Award Number: R01DK138630

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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