OpportunityTitle: Targeting Inflammasomes in Substance Abuse and HIV (R01 Clinical Trial Not Allowed)
AdditionalInformationOnEligibility: Other Eligible Applicants include the following:  Alaska Native and Native Hawaiian Serving Institutions; Asian American Native American Pacific Islander Serving Institutions (AANAPISISs); Eligible Agencies of the Federal Government; Faith-based or Community-based Organizations; Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Indian/Native American Tribal Governments (Other than Federally Recognized); Non-domestic (non-U.S.) Entities (Foreign Organizations); Regional Organizations; Tribally Controlled Colleges and Universities (TCCUs) ; U.S. Territory or Possession.
Description: Neuroinflammation triggered by brain trauma, neurodegenerative diseases and neurotoxicant-induced CNS disorders initiates CNS innate immune responses that activate inflammasomes. Inflammasomes are high molecular weight complexes in the cytosol of stimulated immune cells that mediate the activation of inflammatory cascades. In response to insults, Nod-like receptors (NLRs) recruit adaptor proteins and caspase-1 to assemble inflammasomes and process the release of pro-inflammatory cytokines IL-1?, IL-18 and IL-33. Recent evidence suggests that chronic drug exposure, i.e., cocaine, methamphetamine and morphine, can induce inflammasome activation primarily mediated by NLRP3 within microglia. Additionally, emerging data suggest that HIV-1 infection can also prime inflammasome activation. Drug abuse, especially in association with HIV-1 infection, induces ROS production, impairs blood brain barrier integrity, and promotes monocyte transmigration. These upstream events exert synergistic effects that prime oligomerization and activation of inflammasome and release of pro-inflammatory cytokine IL-1?. The scientific objective of this research is to delineate the role of inflammasomes in neuropathology produced by chronic drug exposure and HIV infection. Understanding the involvement of inflammasome in the immune activation may help identify molecular markers and immune cells associated with HIV-1 disease progression among substance abuse populations, and identify novel targets for intervention to treat neuroinflammation and immune dysregulation aroused in these processes.
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