Thursday, April 25, 2024 4/25/2024

Functional Interrogation of Non-Coding Type 1 Diabetes Risk Variants in Human Immune Cells and Beta Cells

Award Number: DP3DK111914
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

PROJECT SUMMARY/ ABSTRACT Type 1 Diabetes (T1D) is a complex autoimmune disease that commonly afflicts children. We need to identify the underlying pathogenic cellular pathways in order to develop effective therapies for this disease. Human genetics has the potential to provide an unbiased view of the causative disease mechanisms. T1D already has been the subject of intensive genetic investigations, including genome-wide association studies (GWAS) that have uncovered dozens of risk loci. However, mechanistic understanding of these risk loci has been a challenge because the vast majority falls outside of genes, in non-coding regions of the genome. In contrast to protein- coding regions of the genome where we understand the amino acid code, we still do not have a clear framework to understand how non-coding genome variants alter cell function and contribute to disease. To learn how DNA variation throughout the genome affects cellular pathways and contributes to T1D, we now need a deeper understanding of the function of non-coding genome elements in the specific cell types that drive the pathology. We propose an integrated strategy to pinpoint the molecular and cellular effects of T1D risk variants. We will perform a population-based study of how natural genetic variation alters the transcriptional and epigenomic state of human immune cells in vivo. We have unique access to human T subsets sorted directly out of the pancreatic draining lymph nodes of organ donors with and without T1D. We will identify specific gene regulatory circuits in T cells that are disrupted as a result of T1D risk variants at the site of inflammation. These studies will be complemented by rigorous functional testing of candidate causal variants in primary human and mouse cells. We will leverage our recent genome editing advances to alter specific disease-associated genome sequences and directly test effects on gene regulation, cell differentiation and murine models of T1D. We will generate isogenic edited primary human and mouse T cells to validate mechanistic effects of T1D variants. To test the hypothesis that a subset of T1D variants impairs beta cells, we will also edit human ES cells and assess direct effects on in vitro beta cell differentiation and function. Understanding how causal non-coding T1D risk variants disrupt key gene programs in human cells has potential to accelerate development of targeted therapeutic approaches.


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: 2022 ( Subtotal = -$1 )
2022	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	10/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1
2022	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	11/5/2021	NEW	$0
2022	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	11/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	10/1/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	11/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$1

Issue Date FY: 2021 ( Subtotal = -$63,600 )
2021	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/4/2021	NEW	-$87,804
2021	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/18/2021	NEW	-$481,705
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/19/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$418,105
2021	2016	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	5/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,804
														Subtotal = -$63,600

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/22/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $3,764,602 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/19/2016	NEW	$3,764,602
														Subtotal = $3,764,602

Grand Total All Awards = $3,701,001

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Functional Interrogation of Non-Coding Type 1 Diabetes Risk Variants in Human Immune Cells and Beta Cells

Award Number: DP3DK111914

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer