THE EFFECTS OF APOE GENOTYPE IN HOMEOSTATIC MICROGLIAL FUNCTION IN PRECLINICAL APOE MOUSE MODEL - PROJECT S…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Assistance award details
- Assistance award identifier
- ASST_NON_K00AG097121_075
- FAIN
- K00AG097121
- Recipient
- UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.372
- Total obligated
- $183,085
- Period
- Sep 6, 2023 – May 31, 2029
- Fiscal year
- 2025
- Place of performance state
- TX
- Source file
- FY2025_All_Assistance_Full_20261006.zip
Description
THE EFFECTS OF APOE GENOTYPE IN HOMEOSTATIC MICROGLIAL FUNCTION IN PRECLINICAL APOE MOUSE MODEL - PROJECT SUMMARY ALZHEIMER'S DISEASE (AD) IS A DEVASTATING NEURODEGENERATIVE CONDITION. AGING AND THE ï¥4 ALLELE OF THE APOE GENE ARE THE STRONGEST GENETIC RISK FACTOR FOR AD. APOE IS THE MAIN CHOLESTEROL TRANSPORTER IN THE BRAIN THAT PROMOTES NEURONAL GROWTH, DEBRIS CLEARANCE, AND IT IS MAINLY PRODUCED BY ASTROCYTES. UPON INFLAMMATORY INSULTS APOE IS PRODUCED BY MICROGLIA TO ACT AS AN IMMUNOMODULATOR. CHRONIC INFLAMMATION EXACERBATES THE PROGRESSION OF AD PATHOLOGY. PREVIOUS STUDIES SHOW AN EFFECT OF APOE4 GENOTYPE IN DECREASED LEVELS OF APOE PROTEIN IN THE BRAIN, INCREASED INFLAMMATION AT BASELINE, AND SIMPLIFICATION OF DENDRITIC SPINES. THE STUDIES PROPOSED HERE AIM TO UNDERSTAND APOE4-RELATED ALTERATION IN MICROGLIAL FUNCTION PRIOR AD ONSET. WE GENERATED A NOVEL HUMAN APOE KNOCK-IN MICE EXPRESSING GFP UNDER THE CX3CR1 PROMOTER TO STUDY THE EFFECTS OF APOE GENOTYPE IN HOMEOSTATIC MICROGLIA FUNCTION. SO FAR IN MY THESIS, I HAVE EXAMINED THE DISTURBANCES OF APOE4 IN HOMEOSTATIC MICROGLIAL FUNCTION AND FOUND THAT APOE4 ALTERED MICROGLIA SURVEILLANCE AND RESPONSE TO DAMAGE THROUGH THE DOWNREGULATION OF CHEMOTACTIC PURINERGIC RECEPTORS. I HAVE ALSO STUDIED THE EFFECTS OF AGING, SEX, AND APOE GENOTYPE IN MICROGLIAL FUNCTION AND FOUND THAT AGING AFFECTS MICROGLIA RESPONSE TO DAMAGE, AND THESE ALTERATIONS OCCUR EARLIER IN APOE4 BRAINS. THIS F99/K00 PROPOSAL WILL ENCOMPASS 2 AIMS PRESENTED IN THE FOLLOWING RESEARCH PLAN. IN AIM 1, I WILL IDENTIFY THE MOLECULAR MECHANISM UNDERLYING MICROGLIAL ALTERATION IN HOMEOSTATIC FUNCTION AND RESPONSE TO AMYLOID ï¢ (Aï¢). AIM 1A WILL EXAMINE WHOLE TRANSCRIPTOME RNA-SEQ FROM APOE3 AND APOE4 MICROGLIA. WE WILL IDENTIFY GENES DIFFERENTIALLY EXPRESSED IN APOE3 AND APOE4 MICROGLIA AND INVESTIGATE SPECIFIC PATHWAYS INVOLVED IN ALTERING HOMEOSTATIC MICROGLIAL FUNCTION. AIM 1B WILL EXAMINE THE EFFECTS OF APOE GENOTYPE ON MICROGLIA'S ABILITY T