Project Grant F31ES038471

OVARIAN HORMONE AND GPER SIGNALING REGULATION OF WILDFIRE SMOKE-INDUCED NEUROINFLAMMATION - PROJECT SUMMARY: WILDFIRE SMOKE (WS) EXPOSURE IS AN ESCALATING PUBLIC HEALTH CONCERN IN THE UNITED STATES, WITH WILDFIRE EVENTS BECOMING MORE FREQUENT AND SEVERE. WS IS A POTENT SOURCE OF FINE PARTICULATE MATTER AND COMBUSTION BYPRODUCTS KNOWN TO INDUCE OXIDATIVE STRESS, DISRUPT IMMUNE HOMEOSTASIS, AND TRIGGER NEUROINFLAMMATORY SIGNALING. ALTHOUGH EPIDEMIOLOGICAL EVIDENCE SUGGESTS THAT WS EXPOSURE IS ASSOCIATED WITH INCREASED RISK OF COGNITIVE IMPAIRMENT AND NEURODEGENERATIVE DISEASE, THE BIOLOGICAL MECHANISMS THAT DRIVE CENTRAL NERVOUS SYSTEM (CNS) VULNERABILITY, PARTICULARLY IN FEMALES UNDERGOING OVARIAN HORMONE DECLINE CONCURRENT WITH MENOPAUSE AND AGING REMAIN POORLY DEFINED. THE MENOPAUSAL TRANSITION IS CHARACTERIZED BY A PROGRESSIVE LOSS OF CIRCULATING ESTROGEN AND PROGESTERONE, BOTH OF WHICH PLAY ESSENTIAL ROLES IN REGULATING NEUROIMMUNE, GLIAL, AND CEREBROVASCULAR FUNCTION. THE DECLINE OF THESE HORMONES MAY SENSITIZE THE BRAIN TO ENVIRONMENTAL EXPOSURES, YET NO STUDIES HAVE COMPREHENSIVELY EXAMINED HOW MENOPAUSAL STAGE OR RECEPTOR-SPECIFIC ESTROGEN SIGNALING SHAPES CNS RESPONSES TO WS. THIS RESEARCH WILL EVALUATE HOW OVARIAN HORMONE LOSS AND G PROTEIN-COUPLED ESTROGEN RECEPTOR (GPER) SIGNALING MODULATE NEUROINFLAMMATORY AND CEREBROVASCULAR RESPONSES TO ACUTE WS EXPOSURE USING TWO COMPLEMENTARY MOUSE MODELS: THE 4-VINYLCYCLOHEXENE DIEPOXIDE (VCD) MODEL OF ACCELERATED OVARIAN FAILURE AND GPER KNOCKOUT (GPER-/-) MICE. AIM 1 DEFINES MENOPAUSAL-STAGE-SPECIFIC CHANGES IN WS-INDUCED CYTOKINE EXPRESSION, GLIAL ACTIVATION, AND TRANSCRIPTIONAL REMODELING ACROSS HIPPOCAMPAL, CORTICAL, AND CEREBELLAR REGIONS USING RT-QPCR, IMMUNOHISTOCHEMISTRY, AND SPATIAL TRANSCRIPTOMICS. AIM 2 INVESTIGATES HOW LOSS OF GPER SIGNALING ALTERS NEUROIMMUNE RESPONSES, CELLULAR PATHWAY ACTIVATION, AND CEREBROVASCULAR ADAPTABILITY FOLLOWING WS EXPOSURE. THESE STUDIES INTEGRATE ENVIRONMENTAL TOXICOLOGY, AND ENDOCRINE PHYSIOLOGY, TO IDENTIFY HORMONE-DEPENDENT MECHANISMS UNDERLYING WS SUSCEPTIBILITY. THE RESULTS WILL ADVANCE UNDERSTANDING OF HOW ENDOCRINE DECLINE INTERACTS WITH AIR POLLUTION EXPOSURE TO INFLUENCE NEUROINFLAMMATORY RISK, WITH IMPLICATIONS FOR PREDICTING VULNERABILITY DURING THE MENOPAUSAL TRANSITION AND INFORMING POTENTIAL THERAPEUTIC TARGETS TO IMPROVE BRAIN HEALTH IN SMOKE-IMPACTED REGIONS.