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Does post-transcriptional control of NLRP3 inflammasome activity impact development of type 1 diabetes?

Award Number: R21AI149171
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Does post-transcriptional control of NLRP3 inflammasome activity impact development of type 1 diabetes? - The human genome contains a large number of cis- and trans-acting regulatory elements that modulate gene activity at different points in the progression from gene transcription to translation. Alterations in non-coding or regulatory regions of the genome are linked to autoimmune type 1 diabetes (T1D) in Genome-wide association studies (GWAS), suggesting that changes in gene or gene product expression might play an important role in functional immune dysregulation. We have identified multiple post-transcriptional regulatory elements in the 3Ꞌ-UTR (untranslated region) of NLRP3, a cytosolic innate immune sensor of metabolic dysfunction, that impact NLRP3 mRNA stability and are associated with T1D risk. NLRP3 activation results in assembly of a large oligomeric signaling complex called the inflammasome that promotes a form of inflammatory cell death called pyroptosis and production of bioactive IL-1β, a pro-inflammatory cytokine implicated in the pathophysiology of T1D. In the NOD (non-obese diabetic) mouse model, NLRP3 deficiency protects from development of T1D through impaired production of IL-1β and reduced migration of pathogenic T cells to the pancreatic islets, suggesting a critical role for the NLRP3 inflammasome in T1D pathogenesis. While this set of linked events is well described, little is known about the post-transcriptional mechanisms that control the expression NLRP3 and set the threshold for inflammasome activation and the pathological events associated with development of T1D. Our genetic data document that a single nucleotide polymorphism in the 3Ꞌ-UTR of the human NLRP3 gene that functionally increases NLRP3 mRNA is significantly associated with T1D risk suggesting that an increase in NLRP3 may play a role in disease development. We have found that the NLRP3 gene also has two polyadenylation sites, which either encode for a stable short 3Ꞌ-UTR or a less stable longer 3Ꞌ-UTR. The longer 3Ꞌ-UTR harbors several cis acting regulatory motifs, such as AU-rich elements, miRNA binding sites and gamma interferon inhibitor of translation elements, which are known to suppress protein expression. Based on these data we hypothesize that preferential usage of the short 3'-UTR as opposed to the long 3'-UTR increases the gene dosage of NLRP3 thereby sensitizing cells to NLRP3 activators and lowering the threshold for NLRP3 inflammasome activation in T1D. In this grant we will generate mice carrying the short vs. long 3'-UTR variants of NLRP3 on the NOD background with the goal of dissecting the impact of gene dosage of NLRP3 via alternate 3Ꞌ-UTR usage on the development and progression of T1D in vivo. Our study will generate foundational mouse models to study the role of post-transcriptional regulation in development of T1D and will have broader implications for understanding how expression changes caused by genetic variation impact the development of complex autoimmune diseases like T1D.


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: 2025 ( Subtotal = -$2,651 )
2025	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	11/22/2024	NON-COMPETING CONTINUATION	-$2,651
														Subtotal = -$2,651

Issue Date FY: 2022 ( Subtotal = $247,044 )
2022	2022	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/17/2022	NON-COMPETING CONTINUATION	$247,044
														Subtotal = $247,044

Issue Date FY: 2021 ( Subtotal = $292,384 )
2021	2021	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	5/11/2021	NEW	$292,384
														Subtotal = $292,384

Grand Total All Awards = $536,777

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Does post-transcriptional control of NLRP3 inflammasome activity impact development of type 1 diabetes?

Award Number: R21AI149171

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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