IL17 signaling in monogenic type 1 diabetes
Active Project Grant Awarded Last action
- Award ID
- R21AI191139
- Recipient
-
The Regents Of The University Of California. San Francisco UEI KMH5K9V7S518
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $451,000
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 78% complete
- Place of performance
- San Francisco, CA 94143, USA
Award details come from USAspending.gov.
Description
- Abstract
- This proposal's objective is to determine whether genetic mutations that alter IL-17 signaling contribute to the etiology of autoimmune diabetes. Autoimmune diabetes is characterized by circulating autoantibodies and infiltrating autoreactive lymphocytes into the pancreatic islet, eventually leading to β-cell failure and death. Studies of individuals and families with suspected monogenic forms of autoimmune diabetes provide a unique opportunity to understand novel pathways in human biology. For example, type 1 diabetes (T1D) is a frequent feature in patients with deleterious mutations in aire and FOXP3. Dissecting the consequences of these mutations has improved our understanding of the mechanisms underlying immune tolerance and how perturbations to these mechanisms results in organ-specific autoimmune disease, such as T1D. Over the last decade, rapid advances in genetic sequencing have allowed for a deeper exploration and discovery of rare variants that are linked to disease with techniques like whole exome sequencing. Using this approach in both kindreds and rare outlier patient populations, there has been expanding discovery of mutations in other pathways with a link to T1D that include CTLA4, lrba, STAT1 and STAT3. We identified families with multigenerational type 1 diabetes and candidate mutations in IL17RC and IL17C. These mutations were not found in more than 270,000 alleles in the genome aggregation database (gnomad) database and have a cadd score ("combined annotation dependent depletion", a widely used tool for predicting the deleteriousness of single nucleotide variants) of >20, which places these in the top 0.5% of deleterious mutations in humans. Our preliminary data suggest that these are gain-of-function mutations and that their constitutive activity results in autocrine inflammatory signaling loop in pancreatic β cells. We propose to test this model using both in vitro and in vivo approaches. If successful, these studies will enable US to understand the mechanism by which altered IL-17 signaling leads to autoimmune diabetes.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $164,000 | |
| Original award | $287,000 |
Quick answers
Who received award R21AI191139?
R21AI191139 was awarded to The Regents Of The University Of California. San Francisco by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on April 25, 2025.
How much is award R21AI191139 worth?
$451,000 has been obligated on R21AI191139.
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