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Mechanisms of STING-driven autoinflammation

Award Number: R01HL165787
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Mechanisms of STING-driven autoinflammation - Cyclic GMP-AMP synthase (cGAS) detects foreign DNA during infection or self-DNA leading to autoinflammatory diseases such as Aicardi-Goutieres syndrome. cGAS signals via STING, a receptor for cyclic GMP-AMP generated by cGAS. A series of gain-of-function mutations resulting in constitutive activation of STING have been associated with a debilitating autoinflammatory disease called STING-Associated- Vasculopathy with onset in Infancy (SAVI). SAVI patients suffer from severe vasculitic lesions and interstitial lung disease (ILD) and frequently succumb to respiratory failure. Like the lung conditions associated with other autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, very little is known about the mechanisms that promote inflammation in these patients. To gain insights into the mechanisms of STING driven inflammation in the lung, we have developed a murine model for the most common SAVI mutation, STINGV154M (VM), and found that mice heterozygous for this mutation develop immune abnormalities and lung disease. Lung endothelial cells are among the highest STING-expressing cells in the lung and based on our preliminary data we believe that auto-inflammation in the VM lung results from the direct effects of the SAVI mutation on “initiator” radioresistant cells (endothelial cells, and/or fibroblasts) resulting in stromal cell activation, differentiation, chemokine production and expansion. Lymphocytes (VM or WT) are then recruited to the lung. The recruited effector T cells further promote the pathogenic activity of both radioresistant cells and myeloid cells, leading to chronic inflammation; IFN plays a key role in this process. How the VM SAVI allele mediate disease pathogenesis in stromal cells remains unknown. We will focus on STING activation in endothelial cells and how these events lead to lymphocyte recruitment, activation and pathology. Aim 1 will determine the lymphocyte- independent effect of SAVI mutations on lung innate immune function. Aim 2 will define the role of infiltrating T cells in the development of VM ILD while Aim 3 will define VM-driven signaling events in ECs and the impact of STING-targeted therapeutics on ILD. There is an urgent need to identify better therapies for patients afflicted with autoimmune and autoinflammatory lung disorders and the studies proposed in this application should provide critical insights that will enable us to design the best therapies. Further, these studies will also provide an opportunity to study the impact of STING activation on stromal cell types more generally, an emerging area of research as STING activity in endothelial cells has recently been linked to the development of severe COVID19.


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 = $837,240 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Lung Diseases Research	000	3	7/2/2025	NON-COMPETING CONTINUATION	$837,240
														Subtotal = $837,240

Issue Date FY: 2024 ( Subtotal = $820,495 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Lung Diseases Research	000	2	5/22/2024	NON-COMPETING CONTINUATION	$820,495
														Subtotal = $820,495

Issue Date FY: 2023 ( Subtotal = $837,240 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Lung Diseases Research	000	1	5/15/2023	NEW	$837,240
														Subtotal = $837,240

Grand Total All Awards = $2,494,975

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Mechanisms of STING-driven autoinflammation

Award Number: R01HL165787

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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