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RICTOR dependent microglial polarization in aging

Award Number: R36AG062961
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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RICTOR dependent microglial polarization in aging - Aging is the primary risk factor for most neurodegenerative disorders including Alzheimer's disease (AD). The dysfunction seen in organisms because of aging has a multifaceted origin at the molecular level. Understanding how altered molecular signaling in key cellular pathways generates age-related decline is essential to develop better, more targeted therapies that ameliorate dysfunction. AD and related diseases are the most crippling cognitive threat to our aging population. There is no cure for AD, and this is partly due to a poor understanding of how aging and inflammation impact pathogenesis and neural plasticity. It is imperative that we gain a more comprehensive understanding of the biological basis for brain aging. We hypothesize that the neuroimmune system plays a critical role in aging pathology. Microglia are the brain's resident macrophage and the major immune effector in the CNS. “Activated” microglia assume a pro-inflammatory phenotype, secreting cytotoxic factors. An additional process mediated by anti-inflammatory molecules, inhibits the pro- inflammatory phenotype and shifts microglial toward a restorative phenotype that promotes debris clearance and tissue repair. Aging perturbs microglial biology such that aging microglia become hyper-responsive to pro- inflammatory stimuli, generate excess cytotoxic factors, and become insensitive to anti-inflammatory molecules. Aged microglia are also increasingly unable to assume an anti-inflammatory phenotype. In this way, dysfunctional microglia become neurotoxic and increase CNS vulnerability. We have previously described age- related changes in rodent microglia using mass-spectrometry-based proteomics. We identified RICTOR, a subunit of mTORC2, as an upstream regulator predicted to be inhibited with age. This prediction coincided with upregulated pro-inflammatory signaling, downregulated anti-inflammatory signaling, and impaired cellular metabolism and energy regulation. We validated this finding by demonstrating reduced RICTOR expression in aged primary mouse microglia when compared with their younger counterparts. We also conducted targeted knockdown of RICTOR in BV2 cells and observed a phenotype resembling aged microglia, validating a primary role for RICTOR in the aging phenotype. The present study will determine the consequences of RICTOR knockdown in vivo on microglial phenotype and cognitive behavior in young mice. We hypothesize that in vivo microglial RICTOR deletion will induce an aging microglial phenotype that will decrease brain resilience and have widespread impact on cognition and neural plasticity. We predict that knockout animals will manifest a phenotype characterized by dysregulated neuroinflammation, impaired cognitive and behavioral performance, and reduced brain plasticity. Our goal is to identify the molecular substrates of in vivo microglial dysfunction via mTORC2 signaling with the experiments detailed in the proposal.


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: 2023 ( Subtotal = -$100 )
2023	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	11/8/2022	NON-COMPETING CONTINUATION	-$100
														Subtotal = -$100

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	9/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $67,819 )
2020	2020	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	2	3/27/2020	NON-COMPETING CONTINUATION	$67,819
														Subtotal = $67,819

Issue Date FY: 2019 ( Subtotal = $67,066 )
2019	2019	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Aging Research	000	1	4/12/2019	NEW	$67,066
														Subtotal = $67,066

Grand Total All Awards = $134,785

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RICTOR dependent microglial polarization in aging

Award Number: R36AG062961

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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