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The role of SH2B3 in regulating CD8 T cells in Type 1 Diabetes

Award Number: R03DK134746
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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The role of SH2B3 in regulating CD8 T cells in Type 1 Diabetes - PROJECT SUMMARY/ABSTRACT This project is a small grant program R03 application for Dr. Eric Allenspach, an Assistant Professor in the Department of Pediatrics at the University of Washington (UW). He is a recipient of an NIH Mentored Clinical Scientist Research Career Development Award (K08) from the NIDDK and is currently in year four. Dr. Allenspach is an attending physician in both the divisions of Pediatric Rheumatology and Immunology and has a clinical and research interest in the treatment of pediatric autoimmune conditions. Dr. Allenspach’s specific research interest is understanding the molecular mechanisms regulating autoimmunity including rare variants and risk alleles. His long-term career goal is to become an independently funded principal investigator studying genetic mechanisms of autoimmunity in both animal models and using human samples using basic and translational approaches. In the present application, Dr. Allenspach is requesting NIH R03 funding to support a new area of research related, yet distinct, to his K08. Dr. Allenspach proposes studying the biologic role of an identified autoimmune risk variant in the adaptor protein SH2B3 on the function of T cells in mouse models of type 1 diabetes (T1D). A strong association has been found between a genetic allele (rs3184504) in the SH2B3 gene and T1D. In this proposal, we utilize murine modeling to understand how reduced SH2B3 function affects T cells. The K08 proposal focused on the role of SH2B3 in shaping myeloid development, function and antigen presentation as linked to T1D. Now, preliminary data from our group has identified a clear T cell-intrinsic role for SH2B3 in regulating the IL-2 receptor pathway. A strong association has been found between the genetic risk allele (rs3184504*T) and T1D and this allele encodes for a hypomorphic SH2B3 protein. Deficiency of Sh2b3 in murine CD8 T cells renders them refractory to tolerance mechanisms in vivo as demonstrated in a murine diabetes model. The mechanism driving this autoimmunity is not clear. In this proposal, we will test whether deficiency in SH2B3 alters the TCR signaling threshold required for proliferation and differentiation. We will leverage a well-established murine TCR-transgenic models coupled with TCR signaling reporters and test this in vitro and in vivo. We will explore whether SH2B3 regulates all of the common gamma chain receptors and how this signaling intersects with TCR signaling. We will also test whether SH2B3 deficiency skews toward terminal effector memory cells, a known pathogenic phenotype of CD8 cells associated with T1D progression. These basic studies will help inform the mechanistic understanding of the SH2B3 genetic risk variant in promoting diabetes and can guide future human studies. It is anticipated these studies would provide the publications and preliminary data needed to develop an independent research direction and apply for R01 funding at the end of the career development support.


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 = $0 )
2025	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $141,768 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/29/2024	NON-COMPETING CONTINUATION	$132,908
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/2/2024	NON-COMPETING CONTINUATION	$8,860
														Subtotal = $141,768

Issue Date FY: 2023 ( Subtotal = $147,675 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/30/2023	NEW	$147,675
														Subtotal = $147,675

Grand Total All Awards = $289,443

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The role of SH2B3 in regulating CD8 T cells in Type 1 Diabetes

Award Number: R03DK134746

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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