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Genetic regulation of intestinal epithelial cell innate immune signaling in human type 1 diabetes

Award Number: R21AI130970
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Abstract/Summary Type 1 Diabetes (T1D) is an autoimmune disease with both genetic and environmental contributions, yet a single environmental factor has yet to be identified. We propose that rather than the specific identity of the environmental factor, the way in which an environmental signal is received is most important to disease. Among individuals at risk of developing T1D, seroconversion to islet autoantibody (IA) production is the best and earliest biological predictor of disease progression. Thus, critical events leading to the destructive ß cell autoimmunity associated with T1D are linked to the development of IAs. In subjects with high risk HLA alleles, 9 gene regions marked by single nucleotide polymorphisms (SNPs) are associated with IA seroconversion. Our collaborator’s analysis of these IA risk loci reveals enrichment for genes/proteins that regulate only three cell signaling pathways (RAS/MAPK, PI3K/AKT and JAK/STAT), whereby four IA seroconversion risk variants (PTPN22, SH2B3, ERBB3 and UBASH3A) each impact all three. Thus, we propose that regulation of environmental sensing is at least in part controlled by the one or more of these risk variants associated with the development of IAs. Appropriate communication of the gastrointestinal tract (GI) with the environment is required for local and systemic immunologic homeostasis, which is in part regulated by the intestinal epithelial cell (IEC) through their physical and biochemical interactions with innate and adaptive immune populations. To this end, contribution of immunity within the GI tract to the expression of autoimmunity at distal sites has been previously demonstrated. Thus we propose that the seroconversion risk variants affect immune signaling pathways within the IEC contributing to the maintenance of autoimmunity in T1D, through the secondary expansion and/or polarization of autoreactive effector T-cells. To study human disease, a major need is cell-specific human isogenic systems that can be used to dissect the role of individual T1D risk gene variant alleles. Our preliminary studies support use of a disease-in- a-dish strategy that pairs human induced pluripotent stem cells (iPSCs) with CRISPR/Cas9 gene modification to fulfill these needs. We propose to couple iPSCs and CRISPR/Cas9 technology with our method of reproducible primary human IECs culture to achieve haploinsufficient, mono-allelic homozygosity at risk or protective alleles to evaluate alterations in IEC-immune mechanisms which contribute to the maintenance of ßcell autoimmunity.


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: 2021 ( Subtotal = -$684 )
2021	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	4	7/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$684
														Subtotal = -$684

Issue Date FY: 2020 ( Subtotal = $7,934 )
2020	2019	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	000	3	11/15/2019	NON-COMPETING CONTINUATION	-$64,383
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	005	4	4/24/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$140,966
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	4	11/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$72,317
2020	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	003	4	1/27/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	002	3	11/20/2019	NON-COMPETING CONTINUATION	$0
2020	2019	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	004	3	4/24/2020	NON-COMPETING CONTINUATION	-$140,966
														Subtotal = $7,934

Issue Date FY: 2019 ( Subtotal = $212,699 )
2019	2019	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	000	3	12/4/2018	NON-COMPETING CONTINUATION	$212,699
														Subtotal = $212,699

Issue Date FY: 2018 ( Subtotal = $190,625 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	1	7/30/2018	NEW	-$89,680
2018	2018	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	004	2	8/22/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$55,104
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	1	1/5/2018	NEW	$190,625
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	1	8/22/2018	NEW	-$55,104
2018	2018	EAST CAROLINA UNIVERSITY	1000 E 5TH ST	GREENVILLE	NC	27858	PITT	USA	Allergy and Infectious Diseases Research	002	2	7/31/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$89,680
														Subtotal = $190,625

Grand Total All Awards = $410,574

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Genetic regulation of intestinal epithelial cell innate immune signaling in human type 1 diabetes

Award Number: R21AI130970

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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