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RGS10 regulation of inflammatory signaling

Award Number: R56NS109303
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2019
PERIOD OF PERFORMANCE END DATE: 07/14/2021

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RGS10 regulation of inflammatory signaling - Chronic activation of microglia is a driving factor in the progression of neuroinflammatory diseases, and mechanisms that regulate microglial inflammatory signaling are potential targets for novel therapeutics. RGS10 strongly suppresses inflammatory signaling in microglia, and loss of RGS10 enhances inflammatory neurotoxicity. More specifically, RGS10 suppresses expression of inflammatory genes Tumor Necrosis Factor α (TNFα) and cyclooxygenase 2 (COX-2), following stimulation of Toll-like Receptor 4 (TLR4) by Lipopolysaccharide (LPS). However, the mechanism by which RGS10 affects inflammatory signaling is unknown and is independent of its canonical G protein targeted mechanism. We have identified a robust, novel interaction between RGS10 and the endoplasmic reticulum (ER) localized calcium sensor STIM2 in microglial cells. STIM2 is a critical component of the store-operated calcium entry (SOCE) machinery, responsible for coupling depletion of ER calcium stores with Orai channel-mediated extracellular calcium entry. STIM2-Orai activity regulates inflammatory signaling through activation of the phosphatase calcineurin and its substrate Nuclear Factor of Activated T cells (NFAT), a transcription factor that directly regulates expression of TNFα and COX-2. This pathway provides a novel, plausible mechanism for G protein independent regulation of inflammatory gene expression by RGS10. The goal of this proposal is to define the specificity, mechanisms, and functional consequence of RGS10 interaction with STIM2 in microglia. In preliminary experiments, we have validated RGS10-STIM2 interaction in multiple cell types and demonstrated that inhibition of STIM2, Orai channels, or calcineurin strongly blocks the effect of RGS10 on LPS-stimulated COX-2 expression. We have also demonstrated a marked increase in SOCE in RGS10 knockout microglia. We hypothesize that RGS10 inhibits LPS-stimulated expression of COX-2 and TNFα by interacting with STIM2 at the ER and inhibiting the ability of STIM2 to activate plasma membrane Orai channels and subsequent calcium dependent activation of calcineurin and NFAT. We will 1. Define the structural and scaffolding requirements for STIM2-RGS10 interactions in microglia. This aim will provide essential molecular details governing the novel interaction between RGS10 and STIM2. 2. Define the role of STIM2 and downstream signaling in RGS10 regulation of inflammatory gene expression. This aim will establish to what extent regulation of the STIM2-ORAI-Calcinurin pathway accounts for RGS10’s ability to regulate G protein-independent inflammatory gene expression in microglia. 3. Define the ability of RGS10 to regulate store-operated calcium signaling. This aim will establish a mechanism for RGS10 regulation of SOCE. 4. Define the ability of Gi to regulate RGS10 regulation of STIM2 signaling. This aim will define the mutual regulation of RGS10 interactions with Gi and STIM2 pathways. Completion of these studies will fundamentally shape understanding of RGS10’s role in cell physiology and disease, and will establish unexpected, novel interfaces and activities as therapeutic targets in neuroinflammatory disease.


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: 2022 ( Subtotal = -$4,010 )
2022	2019	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/9/2021	NEW	-$4,010
														Subtotal = -$4,010

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/20/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $523,260 )
2019	2019	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/4/2019	NEW	$523,260
														Subtotal = $523,260

Grand Total All Awards = $519,250

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RGS10 regulation of inflammatory signaling

Award Number: R56NS109303

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2019

PERIOD OF PERFORMANCE END DATE: 07/14/2021

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