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A generic and immunological investigation of JAK-STAT in the pathogenesis of Celiac

Award Number: K08DK128631
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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A generic and immunological investigation of JAK-STAT in the pathogenesis of Celiac - The proposal details a comprehensive five years training program to expand my skills as a physician-scientist. The research plan is focused on JAK-STAT pathway in Celiac Disease (CeD), but the training plan includes extensive didactics in human subject research, bioinformatics and laboratory-based training on T cell immunology. CeD is an immune mediated gastrointestinal disease that arises in patients with a permissive HLA-DQ2/HLA-DQ8 genetic background. The only available treatment for CeD is to follow a gluten-free diet. Patients with germline gain-of-function (GOF) STAT3 mutations and Down Syndrome have an estimated 40- fold and 5-fold higher risk of CeD, respectively, than the general population, along with a predisposition for other autoimmune diseases, including thyroiditis and Type I Diabetes. Patients with Down Syndrome have three copies of the gene for interferon (IFN) receptors on chromosome 21 and thus constitutive JAK-STAT activation. The central hypothesis is that interferon and cytokines mediated JAK-STAT overactivation may cause loss of T cell tolerance to gluten and an increased risk for CeD. The overall goal of this research is to investigate the mechanism of JAK-STAT activation in the pathogenesis of CeD. To accomplish this, first, we will conduct genetic investigation in 100 index cases with familial CeD and search for genetic variants in the JAK-STAT pathway. We will also expand our cohort of CeD patients with known genetic diseases affecting JAK-STAT activation, include patients with GOF-STAT3 and DS. Second, we will assess the key molecules in the JAK-STAT pathway, including agonists, receptors, STAT and their phosphorylated forms, ISGs in monocyte and CD4+ T cells to identify a molecular signature of active CeD. Third, we will investigate the mechanisms of JAK-STAT overactivation on gluten-specific CD4+ T cells through both single cell RNA-Seq and amplified T cell libraries, followed by testing the functional impact of JAK inhibitors on gluten-specific T cells. The results of this study will delineate JAK-STAT activation and its potential as a therapeutic target for Celiac Disease. Furthermore, through the proposed complementary career development plan, I will gain additional training in clinical investigation on the genetics and immunology of CeD; advanced bioinformatic analysis with RNA-seq; and laboratory-based training in gluten specific CD4+ T cells biology. Throughout this research and career development activities, I will be mentored by a team lead by Dr. Timothy Wang, an internationally recognized physician-scientist and an expert in inflammatory cytokines and their role in human gastrointestinal diseases. I am committed to a career as an independent investigator in patient-oriented translational research; and have designed my training plan to acquire the knowledge and skills needed to make a meaningful and substantial contribution to the field by using a functional genetics approach to discover the therapeutic targets in gastrointestinal 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 = $165,456 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/8/2025	NON-COMPETING CONTINUATION	$165,456
														Subtotal = $165,456

Issue Date FY: 2024 ( Subtotal = $165,456 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	5/1/2024	NON-COMPETING CONTINUATION	$165,456
2024	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	11/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$50,437
2024	2021	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/15/2023	NEW	-$50,437
														Subtotal = $165,456

Issue Date FY: 2023 ( Subtotal = $165,456 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	5/3/2023	NON-COMPETING CONTINUATION	$165,456
2023	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	11/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$165,456
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/18/2022	NON-COMPETING CONTINUATION	-$165,456
														Subtotal = $165,456

Issue Date FY: 2022 ( Subtotal = $165,456 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/29/2022	NON-COMPETING CONTINUATION	$165,456
														Subtotal = $165,456

Issue Date FY: 2021 ( Subtotal = $165,456 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/13/2021	NEW	$165,456
														Subtotal = $165,456

Grand Total All Awards = $827,280

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A generic and immunological investigation of JAK-STAT in the pathogenesis of Celiac

Award Number: K08DK128631

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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