Determining how a single-nucleotide patient mutation in ADAR1 leads to autoinflammation
Active Project Grant Awarded Last action
- Award ID
- F31AI203276
- Recipient
-
The Trustees Of Columbia University In The City Of New York UEI QHF5ZZ114M72
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Place of performance
- New York, NY 10032, USA
Award details come from USAspending.gov.
Description
- Abstract
- The innate immune system must strike a delicate balance to prevent autoinflammation: limited immune surveillance results in susceptibility to infection, while overactivation can cause pathological autoinflammation. A striking example of the immune response in dysfunction is the autoinflammatory disease aicardi-goutières syndrome (AGS), which presents with hallmark neurological symptoms such as seizures, developmental delays, and a type I interferon (IFN) signature in the cerebrospinal fluid without detectable viral infection. One protein implicated in AGS pathology is the ubiquitously expressed enzyme adenosine deaminase acting on RNA 1 (ADAR1), which suppresses double-stranded RNA (DSRNA) formation. DSRNA is immunostimulatory and induces chronic autoinflammation if not properly regulated. Thus, ADAR1 is critical in suppressing autoinflammation induced by endogenous dsrnas, in part by editing adenosines (a) to inosines (I) in dsrnas. A-to-I editing is thought to introduce base-pairing mismatches to reduce double-stranded structure, allowing edited dsrnas to evade recognition by DSRNA sensors. ADAR1 mutations typically cause AGS in a recessive fashion, except for the GLY1007ARG mutation (C.3019G>a, heterozygous)-the single known mutation which presents as dominant. How this mutation causes severe disease through a single mutated copy is unknown; how specific cell types contribute to disease has not been investigated, nor has the effect of the GLY1007ARG (G1007R) mutation on ADAR1 function been fully explored. Given the neurological symptoms of AGS, I aim to examine how the G1007R-ADAR1 mutation affects human neural cells and the mechanism(S) by which the mutation alters ADAR1 function. In aim 1, I will differentiate human embryonic stem cells (HESCS) with a heterozygous G1007R mutation (ADAR1G1007R/WT) into neurons and astrocytes to determine how the mutation impacts the DSRNA burden and inflammatory state of neural cells. In aim 2, I will investigate how the G1007R mutation alters biochemical properties of ADAR1, such as DSRNA editing in cells, DSRNA binding, and dimerization. My overarching hypothesis is that ADAR1G1007R/WT neurons and astrocytes fail to regulate immunostimulatory dsrnas due to decreases in ADAR1-mediated editing. Determining the mechanism(S) by which the G1007R mutation alters ADAR1 function will inform treatment options for AGS patients by illuminating which aspects of ADAR1 function are compromised and suggest new treatment targets. More broadly, this study can deepen our understanding of age-related neurodegenerative diseases such as alzheimer's disease that also exhibit a strong DSRNA-mediated immune response. Additionally, uncovering how the purported dominant negative G1007R-ADAR1 mutant functions can help develop ADAR1 inhibitors for broader therapeutic purposes, such as potentiating cancer immunotherapy.
Quick answers
Who received award F31AI203276?
F31AI203276 was awarded to The Trustees Of Columbia University In The City Of New York by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 25, 2027.
How much is award F31AI203276 worth?
$50,114 has been obligated on F31AI203276.
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