NIH grant: Mitochondrial Impact on Inflammaging and Cognitive Impairment in HIV and Substance Use (1R01DA065085-01)

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NIH grant 1R01DA065085-01: Mitochondrial Impact on Inflammaging and Cognitive Impairment in HIV and Substance Use
Institute: {'code': 'DA', 'abbreviation': 'NIDA', 'name': 'National Institute on Drug Abuse', 'admin_org_id': '12500072', 'admin_funding_url': ''}. PI: Jing  Sun. Award: $698861.
Start: 2026-08-15T00:00:00.
PROJECT SUMMARY
This proposal responds to NIDA RFA-DA-26-009 and aims to characterize the mitochondrial regulation of
inflammaging in immune cells and neurons, along with their translational effects on cognitive function among
people with HIV (PWH) who use substances (SU). It is estimated that 30-60% of PWH will develop cognitive
impairment, which is associated with numerous critical adverse outcomes such as frailty, increased
hospitalization rates, and elevated mortality. Among PWH, persons who inject drugs (PWID) represent one of
the most vulnerable groups for cognitive impairment, as substances like cocaine and heroin exhibit pronounced
neurotoxicity and are directly linked to cognitive decline. A primary cause of cognitive impairment among PWH
is inflammaging, characterized by persistent low-grade inflammation and immune activation. Mitochondria,
central to adenosine triphosphate (ATP) production, regulate bioenergetic processes and signaling pathways
across nearly all organ systems but are susceptible to oxidative stress and inflammation. Our ongoing research
indicates that mitochondrial DNA copy number (mtDNA-CN), a marker of mitochondrial integrity, is associated
with HIV infection, T-cell senescence, and cognitive impairment, and is further reduced by active heroin and
cocaine use. Additionally, mitochondrial genetic variation has been closely linked with multiple aging-related
outcomes specifically in PWH, suggesting interactions between mitochondrial genetics and HIV infection.
Therefore, we hypothesize that mitochondrial function and genetics independently and jointly influence immune
dysfunction and cognitive impairment following HIV infection and substance use. Clarifying the interplay between
these factors may yield therapeutic insights capable of improving brain health among PWH. Our study will
address the following aims: 1) To characterize the association of cell type-specific MT function with immune
dysfunction and cognitive impairment as influenced by HIV and SU; 2) To identify mtDNA genetic variation
associated with immune dysfunction and cognitive impairment, and whether HIV and SU modify these
associations; 3) To quantify the effects of HIV and SU on MT function, inflammaging, and nuclear DNA
methylation in induced pluripotent stem cell (iPSC)-derived cortical neurons from PWIDs.

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