Middle Tennessee Research Institute

CHARACTERIZING THE ROLE OF MITOCHONDRIAL DNA GENETIC VARIANTS AND ENDOPHENOTYPES IN SUD, NEUROLOGIC DISEASES, AND EPIGENETIC AGE AMONG VETERANS WITH AND WITHOUT HIV - THE IMPACTS OF CHRONIC HIV INFECTION AND SUBSTANCE USE DISORDERS (SUD) ON NEUROPATHOGENESIS HAVE BEEN WELL ESTABLISHED IF POORLY UNDERSTOOD MECHANISTICALLY. HIV INFECTION IS ASSOCIATED WITH MILD FORMS OF COGNITIVE IMPAIRMENT AS WELL AS OVERT DEMENTIA, POTENTIALLY RELATED TO DIRECT CENTRAL NERVOUS SYSTEM (CNS) VIRAL INVASION AND ITS IMMUNOLOGIC SEQUELAE, OR EVEN INDIRECT EFFECTS OF EXTRA-CNS INFECTION. EFFECTIVE TREATMENTS THAT SUPPRESS PLASMA HIV REPLICATION MITIGATE BUT DO NOT ELIMINATE THIS NEUROPATHOLOGY. SIMILARLY, SUD CAN HAVE WIDE RANGING NEUROPATHOGENIC EFFECTS DEPENDENT ON THE SUBSTANCE(S) USED, EXTENT OF USE, AND HOST FACTORS. AGE IS A CLEAR PREDICTOR OF NEUROPATHOGENESIS IN BOTH HIV INFECTION AND SUD. AND IN BOTH CASES, MITOCHONDRIA AND MITOCHONDRIAL DNA (MTDNA) HAVE BEEN IDENTIFIED AS POTENTIAL LOCI OF NEUROPATHOLOGY, BUT A DETAILED MECHANISTIC EXPLANATION OF THE ROLE OF THESE SUBLIME ORGANELLES HAS BEEN ELUSIVE. MITOCHONDRIA AND MTDNA ALSO CONTRIBUTE TO MULTIPLE THEORIES OF HUMAN AGING AND HAVE MORE RECENTLY BEEN IDENTIFIED AS HAVING KEY ROLES IN REGULATING HUMAN IMMUNE FUNCTION. THE TEAM ASSEMBLED FOR THIS RESEARCH GRANT PROPOSAL ARE SENIOR INVESTIGATORS WITH DIVERSE EXPERTISE AND ARE WELL POSITIONED TO COLLABORATIVELY UTILIZE AN UNPRECEDENTED RESOURCE - THE MILLION VETERAN PROGRAM (MVP) - TO ADDRESS THE COMPLEX INTERACTIONS OF HIV, SUD, AGING, AND LARGE-SCALE MITOCHONDRIAL MEASURES IN EXPLAINING NEUROPATHOGENESIS AT A POPULATION LEVEL. WE HAVE EXTENSIVE PHENOTYPIC, MITOCHONDRIAL SCIENCE, AND EPIGENETIC ANALYTIC EXPERIENCE THAT WILL BE APPLIED TO ADDRESS AN OVERARCHING HYPOTHESIS: MITOCHONDRIAL GENETIC AND ENDOPHENOTYPE MEASURES (MTDNA COPY NUMBER, HETEROPLASMY, AND GENETIC PATHOGENICITY SCORES) AVAILABLE IN LARGE-SCALE MVP DATA WILL IMPROVE OUR UNDERSTANDING OF RELATIONSHIPS BETWEEN SUD, EPIGENETIC AGE, AND NEUROPATHOLOGICAL PHENOTYPES IN PERSONS WITH HIV. WE PLAN TO TEST THIS HYPOTHESIS THROUGH 2 SPECIFIC AIMS TO BE CARRIED OUT IN MVP. THESE AIMS WILL ASSESS RELATIONSHIPS BETWEEN MTDNA GENETIC VARIANTS AND NEUROLOGIC OUTCOMES IN THE CONTEXT OF SUD AND HIV (AIM 1), AND DETERMINE THE ROLE OF MITOCHONDRIAL ENDOPHENOTYPES IN INFLUENCING EPIGENETIC BIOLOGIC AGE AND NEUROLOGIC OUTCOMES AMONG VETERANS WITH SUD AND HIV (AIM 2).

SMALL HEAT SHOCK PROTEINS IN HUMAN AIRWAY SMOOTH MUSCLE TONE AND PATHOPHYSIOLOGY