Role of the bhlh transcription factor ASCL1 in central tolerance
Ended Project Grant Awarded Last action
- Award ID
- R21AI185776
- 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
- $995,244
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date
- 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 the transcriptional activity of the basic helix-loop-helix (bhlh) transcription factor achaete-scute complex 1 (ASCL1) contribute to the etiology of organ-specific autoimmunity in humans. Transcription factor mutations that result in the misregulation of gene expression are particularly potent drivers of human disease. Studies of individuals and families with suspected monogenic forms of autoimmunity provide a unique opportunity to understand novel pathways in human immune biology and have revealed mutations in thymic transcription factors as potent drivers of autoimmunity. For example, mutations in the autoimmune regulator (aire) gene cause a spectrum of organ- specific autoimmune conditions such as hypoparathyroidism, hypothyroidism, addison's disease (adrenals) and type 1 diabetes (pancreas). Aire is a transcriptional activator that drives the expression of tissue- restricted self-antigens (tsas) in medullary thymic epithelial cells (mtecs) to enable the deletion of autoreactive t cells, a process termed "central tolerance". While aire is critical for central tolerance, the severity and spectrum of organ-specific clinical disease among aire patients, including siblings with identical aire mutations, underscores the existence of disease-modulating variables, including perhaps organ-specific disease-promoting and/or ameliorating genetic elements that modulate aire expression, activity or function. ASCL1, an established bhlh transcription factor that orchestrates the proliferation, specification and differentiation of neural progenitors, was recently reported to be expressed in three human medullary thymic cell subpopulations: two known to be critical for central tolerance, 1) aire+ mtecs and 2) their developmental precursors (aire- mtecs); and 3) a novel subpopulation of thymic neuroendocrine cells. The role of ASCL1 in immune biology and autoimmune disease is completely unknown. We have also identified one individual and two siblings in our ucsf patient registry with suspected monogenic autoimmunity and ASCL1 mutations. The individuals tested negative for known genetic causes of autoimmunity and have rare/predicted deleterious ASCL1 mutations that are adjacently positioned within the transactivation domain of the protein. The novel discovery of ASCL1 expression in the thymus coupled with the identification of suspected ASCL1 monogenic autoimmune patients leads to the general hypothesis for this project. We hypothesize that ASCL1 mutations that alter its transcriptional activity disrupt the development, function, and/or microenvironment of aire+ mtecs, resulting in autoimmunity.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Amendment | $164,000 | |
| Amendment | $28,664 | |
| Amendment | $28,664 | |
| Amendment | $257,972 | |
| Amendment | $257,972 | |
| Original award | $257,972 |
Quick answers
Who received award R21AI185776?
R21AI185776 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 June 13, 2024.
How much is award R21AI185776 worth?
$995,244 has been obligated on R21AI185776.
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