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Effect of delayed microglial specific PPARγ activation on ameliorating chronic neuroinflammation and cognitive dysfunction following r-mTBI

Award Number: R21AG093634
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2026
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Effect of delayed microglial specific PPARγ activation on ameliorating chronic neuroinflammation and cognitive dysfunction following r-mTBI - Brain inflammation is a common feature of repetitive mild TBI mediated neurodegeneration, and this is associated with the maladaptive transformation of microglia from an early neurorestorative phenotype to a persistently dysfunc- tional and chronically activated pro-inflammatory state. Yet, the crucial factors governing the propagation and per- sistence of these diffuse neuroinflammatory responses in the chronic sequelae of TBI remain unknown. To address this, we developed a translationally relevant preclinical model of r-mTBI. Using this model, we generated a molecular library of microglia transcriptomic profiles that provides a detailed time-course of the microglia neuroinflammatory response to TBI. Importantly, we observed deficits in glucose and lipid metabolism, oxidative stress, and a proinflam- matory signature at chronic timepoints, which appeared to be mediated by the loss of constitutive PPAR𝛾 signaling. PPAR𝛾 is expressed in multiple cell types and plays a critical role in regulating glucose and lipid metabolism, and inflammation. Treatment with a PPAR𝛾 agonist has shown efficacy in mitigating cognitive deficits and chronic mi- croglial activation in our r-mTBI model. However, the use of PPAR𝛾 agonists carry several challenges, such as the often reported off-target effects and low BBB penetration. These drugs also lack the specificity needed to target mi- croglial PPARγ signaling, and it remains unknown whether the immunomodulatory effects of PPARγ are carried out by microglia, or other CNS cell-types. Further studies are needed to clarify these cell-specific roles to optimize their therapeutic benefits. We recently developed a Cre-LoxP model that overexpresses constitutively active PPARγ in mi- croglia, and in pilot studies using a pre-injury tamoxifen treatment paradigm, we revealed repression of microglia inflammation and astrogliosis at 30-days post injury (30dpi) and improvement in spatial memory. In this new appli- cation, we will now clarify the constitutive role of PPARγ in the chronic stages of TBI and demonstrate whether delayed PPARg overexpression in adult microglia (at 90dpi) could serve as a novel target for mitigating chronic neuroinflammation and cognitive deficits. In these studies, we will examine functional and pathological outcomes at 180- and 270-dpi. Finally, we will use a flow cytometry and microglial transcriptomic mining approach to compare TBI-dependent responses in the presence or absence of PPARg activation to reveal phenotypic changes in microglia subtypes and neurorestorative mechanisms that correlate with favorable outcomes and represent novel therapeutic targets to block chronic neuroinflammation and the negative consequences of TBI and risk for neurodegenerative diseases. By optimization of the therapeutic effect of boosting PPARγ expression in microglia using our novel induc- ible PPARg model we aim to maximize PPARγ effect and reveal novel tractable targets that result in the same positive downstream consequences of microglial specific PPARγ overexpression in the aftermath of TBI that can then be ex- plored as safer and tolerable novel therapies for TBI. Our long-term goal is to identify molecular mechanisms causing posttraumatic neuroinflammation that contribute to progressive brain degeneration and cognitive impairments, in order to develop effective delayed therapeutic interventions to combat neurological complications linked with TBI.


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: 2026 ( Subtotal = $468,875 )
2026	2026	THE ROSKAMP INSTITUTE, INC.	2040 WHITFIELD AVE	SARASOTA	FL	34243	MANATEE	USA	Aging Research	000	1	12/15/2025	NEW	$468,875
														Subtotal = $468,875

Grand Total All Awards = $468,875

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Effect of delayed microglial specific PPARγ activation on ameliorating chronic neuroinflammation and cognitive dysfunction following r-mTBI

Award Number: R21AG093634

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2026

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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