EXPLORING THE MECHANISMS OF DYSFUNCTIONAL MITOCHONDRIAL QUALITY CONTROL IN CEREBROVASCULAR DISEASE AND THE…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Assistance award details
- Assistance award identifier
- ASST_NON_K00AG079793_075
- FAIN
- K00AG079793
- Recipient
- BRIGHAM & WOMENS HOSPITAL INC
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $191,640
- Period
- Dec 1, 2022 – Jun 30, 2028
- Fiscal year
- 2024
- Place of performance state
- MA
- Source file
- FY2024_All_Assistance_Full_20261006.zip
Description
EXPLORING THE MECHANISMS OF DYSFUNCTIONAL MITOCHONDRIAL QUALITY CONTROL IN CEREBROVASCULAR DISEASE AND THE AGING BRAIN - PROJECT SUMMARY MITOCHONDRIAL DYSFUNCTION IS A PROMINENT ELEMENT OF MANY LEADING CAUSES OF DISABILITY, NAMELY CEREBROVASCULAR AND NEURODEGENERATIVE DISEASES. THE FUNCTION AND STABILITY OF MITOCHONDRIA ARE TIGHTLY REGULATED BY THE MECHANISMS OF MITOCHONDRIAL DYNAMICS AND QUALITY CONTROL (QC). THE DYNAMIC NATURE OF MITOCHONDRIA IS MAINTAINED BY THE BALANCING FORCES OF FISSION AND FUSION. THESE PROCESSES OF MITOCHONDRIAL DYNAMICS OPERATE TO PRESERVE THE FUNCTIONAL ARCHITECTURE OF THE MITOCHONDRIAL NETWORK. THE MECHANISMS OF MITOCHONDRIAL QC, INCLUDING MITOPHAGY, PROTEOSTASIS, AND BIOGENESIS, WORK TO REGULATE THE COMPONENTS OF THE MITOCHONDRIAL NETWORK THROUGH SYNTHESIS AND DEGRADATION. THESE FORCES ACTIVELY CONTROL THE FUNCTIONALITY OF THE MITOCHONDRIAL NETWORK TO ENSURE EFFICIENT ENERGY PRODUCTION. IN CEREBRAL ISCHEMIA/REPERFUSION (I/R) INJURY, THE PROCESSES OF MITOCHONDRIAL DYNAMICS AND QC BECOME DYSREGULATED, CONTRIBUTING TO METABOLIC DYSFUNCTION AND NEUROLOGICAL DAMAGE. THE F99 PHASE OF THIS PROPOSAL AIMS TO IDENTIFY THE PHASES OF DISRUPTED MITOCHONDRIAL DYNAMICS AND QC IN CEREBRAL I/R INJURY, AND THEIR RESPECTIVE MOLECULAR MECHANISMS. UTILIZING ADVANCED TECHNOLOGIES RELATED TO MACHINE LEARNING, COMPUTATIONAL MODELING, AND LIVE CELL IMAGING, I HAVE CREATED AN AGENT-BASED MODEL OF MITOCHONDRIAL DYNAMICS FOR THESE INVESTIGATIONS. THIS MODEL ALLOWS FOR THE SIMULATION OF THE DYNAMIC ACTIONS OF INDIVIDUAL MITOCHONDRIAL UNITS TO CULMINATE IN THE COMPLEX PATTERNS NORMALLY OBSERVED IN MAMMALIAN CELLS. LIVE CELL IMAGING OF MOUSE PRIMARY CORTICAL NEURONS FROM NOVEL TRANSGENIC REPORTER LINES (I.E., MITOTIMER, MITOQC) AND CONDITIONAL KNOCKOUT LINES WILL BE UTILIZED TO OBSERVE THE RESPECTIVE CONTRIBUTIONS OF INDIVIDUAL DYNAMICS PROTEINS TO THE PATTERNS OF MITOCHONDRIAL MORPHOLOGY. KNOCKOUT NEURONS WILL BE EXPOSED TO OXYGEN GLUCOSE DEPRIVATION (OGD), AN IN VIT