R01MH126773

Effects of HIV and ART on Myelination in the Adolescent - Project Summary

Adolescents account for a disproportionately high percentage of new HIV infections each year. In 2018, 30% of all new global infections were among 15-25 year-olds, and 21% of all new United States infections were among 13-24 year-olds. However, we know little about the effects of new infection and therapy on the developing brain in this critical time frame.

Limited studies on HIV+ 18-24 year-olds on and off antiretroviral therapy (ART) demonstrate that up to 65% develop behavioral, cognitive, and motor impairments meeting the criteria for HIV-associated neurocognitive disorder (HAND). This proportion is higher than that seen in older HIV+ adult counterparts, despite lower viremia, higher CD4+ T-cell counts, and shorter durations of infection in adolescents.

A major gap in our knowledge is the mechanistic basis of this dysfunction in the developing central nervous system (CNS). The effect of virus-mediated and/or ART toxicities on normal myelination and synaptic pruning in the adolescent and young adult brain is unknown. It is well documented that functionally critical development of white matter (WM) and synaptic plasticity continues until the mid-twenties in humans.

Interestingly, WM deficits, including myelin lesions, decreased myelin sheath thickness, and abnormal myelin protein expression, are among the persistent pathologic findings in HIV+ adults with HAND. Consistent with pathologic findings, transcriptome analyses of cortical gray matter (GM) and WM from HIV+ adults, both ART-naïve and ART-treated, have revealed decreased expression of genes associated with oligodendrocyte (OL) differentiation and myelination.

We have shown that HIV-associated neuroinflammation inhibits OL maturation through upregulation of the integrated stress response, a pathway shown to be dysregulated in the CNS of HIV+ patients. Furthermore, data from our laboratory also suggest that a subset of antiretroviral (ARV) drugs themselves can disrupt differentiation of OL precursor cells in vitro and remyelination in vivo.

An independent effect of ARV drugs on WM pathology is clinically important not only in the care of HIV+ adolescents but also in uninfected adolescents who use pre-exposure prophylaxis (PrEP), a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), to prevent HIV infection. Our preliminary data indicate that several ARV drugs, including FTC and TDF, inhibit the progression of OL maturation in vitro through lysosomal dysfunction, suggesting a role for organelle stress.

Thus, we hypothesize that HIV, ART, and PrEP disrupt developmental myelination via organelle stress, contributing to the multifaceted CNS deficits observed in adolescents and young adults. We propose to:

1) Determine the mechanisms by which HIV-induced neuroinflammation disrupts OL maturation in adolescents.
2) Determine the role of lysosome dysfunction in ART-induced changes in OL maturation in rodent models of adolescence and young adulthood.
3) Compare OL maturation and myelination measures in aims 1 and 2 to magnetic resonance imaging measures of WM volume and integrity in adolescent rats and a pre-existing cohort of adolescent humans.

Trustees Of The University Of Pennsylvania

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. IN MAY 2020, NIMH RELEASED ITS NEW STRATEGIC PLAN FOR RESEARCH. THE NEW STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH. THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTE'S RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES. THE INSTITUTE'S OVERALL FUNDING STRATEGY IS TO SUPPORT A BROAD SPECTRUM OF INVESTIGATOR-INITIATED RESEARCH IN FUNDAMENTAL SCIENCE, WITH INCREASING USE OF INSTITUTE-SOLICITED INITIATIVES FOR APPLIED RESEARCH WHERE PUBLIC HEALTH IMPACT IS A SHORT-TERM MEASURE OF SUCCESS. THE NEW STRATEGIC PLAN ALSO ADDRESSES A NUMBER OF CROSS-CUTTING THEMES THAT ARE RELEVANT TO ALL RESEARCH SUPPORTED BY NIMH, THESE THEMES HIGHLIGHT AREAS WHERE NIMH-FUNDED SCIENCE MAY HAVE THE GREATEST IMPACT, BRIDGE GAPS, AND OFFER NOVEL APPROACHES TO ACCELERATE ADVANCES IN MENTAL HEALTH RESEARCH. FOR EXAMPLE, NIMH VALUES A COMPREHENSIVE RESEARCH AGENDA THAT TAKES AN INCLUSIVE APPROACH THAT ENSURES RESEARCH INTERESTS ARE VARIED, MAINTAIN DIVERSE PARTICIPATION AND PARTNERSHIPS, AND ACHIEVE RESEARCH GOALS ACROSS MULTIPLE TIMEFRAMES. THIS INCLUDES DIVERSE METHODOLOGIES, TOOLS, AND MODELS, RESEARCH ADDRESSING COMPLEX BASIC, TRANSLATIONAL, AND APPLIED QUESTIONS, RESEARCH INCLUDING BOTH SEXES AND, AS APPROPRIATE, GENETIC BACKGROUND, AND, PARTICIPANTS FROM DIVERSE RACIAL AND ETHNIC BACKGROUNDS, AND ACROSS GENDER IDENTITIES, GEOGRAPHICAL CONTEXT, SOCIOECONOMIC STATUS, NEUROTYPE, AND AGE OFFERING THE BEST POSSIBLE REPRESENTATION, FOR THE BROADEST NUMBER OF INDIVIDUALS WHO MAY ULTIMATELY BENEFIT FROM THESE SCIENTIFIC ADVANCES. TO ACCOMPLISH THE GOALS OUTLINED IN THE NEW STRATEGIC PLAN, NIMH WILL SUPPORT RESEARCH THAT AIMS: TO CHARACTERIZE THE GENOMIC, MOLECULAR, CELLULAR, AND CIRCUIT COMPONENTS CONTRIBUTING TO BRAIN ORGANIZATION AND FUNCTION, TO IDENTIFY THE DEVELOPMENTAL, FUNCTIONAL, AND REGULATORY MECHANISMS RELEVANT TO COGNITIVE, AFFECTIVE, AND SOCIAL DOMAINS, ACROSS UNITS OF ANALYSIS, AND, TO GENERATE AND VALIDATE NOVEL TOOLS, TECHNIQUES, AND MEASURES TO QUANTIFY CHANGES IN THE ACTIVITY OF MOLECULES, CELLS, CIRCUITS, AND CONNECTOMES. TO DISCOVER GENE VARIANTS AND OTHER GENOMIC ELEMENTS THAT CONTRIBUTE TO THE DEVELOPMENT OF MENTAL ILLNESSES IN DIVERSE POPULATIONS, TO ADVANCE OUR UNDERSTANDING OF THE COMPLEX ETIOLOGY OF MENTAL ILLNESSES USING MOLECULAR EPIDEMIOLOGIC APPROACHES THAT INCORPORATE INDIVIDUAL GENETIC INFORMATION IN LARGE COHORTS, TO ELUCIDATE HOW HUMAN GENETIC VARIATION AFFECTS THE COORDINATION OF MOLECULAR, CELLULAR, AND PHYSIOLOGICAL NETWORKS SUPPORTING HIGHER-ORDER FUNCTIONS AND EMERGENT PROPERTIES OF NEUROBIOLOGICAL SYSTEMS, AND, TO DEVELOP NOVEL TOOLS AND TECHNIQUES FOR THE ANALYSIS OF LARGE-SCALE GENETIC, MULTI-OMIC DATA AS IT APPLIES TO MENTAL HEALTH. TO UTILIZE CONNECTOMIC APPROACHES TO IDENTIFY BRAIN NETWORKS AND CIRCUIT COMPONENTS THAT CONTRIBUTE TO VARIOUS ASPECTS OF MENTAL FUNCTION AND DYSFUNCTION, TO DETERMINE THROUGH BRAIN-WIDE ANALYSIS HOW CHANGES IN THE PHYSIOLOGICAL PROPERTIES OF MOLECULES, CELLS, AND CIRCUITS CONTRIBUTE TO MENTAL ILLNESSES, TO DEVELOP MOLECULAR, CELLULAR, AND CIRCUIT-LEVEL BIOMARKERS OF IMPAIRED NEURAL FUNCTION IN HUMANS, AND, TO DEVELOP INNOVATIVE TECHNOLOGIES, INCLUDING NEW IMAGING, COMPUTATIONAL, PHARMACOLOGICAL, AND GENETIC TOOLS TO INTERROGATE AND MODULATE CIRCUIT ACTIVITY AND STRUCTURE ALTERED IN MENTAL ILLNESSES. TO ELUCIDATE THE MECHANISMS CONTRIBUTING TO THE TRAJECTORIES OF BRAIN DEVELOPMENT AND BEHAVIOR, AND, TO CHARACTERIZE THE EMERGENCE AND PROGRESSION OF MENTAL ILLNESSES, AND IDENTIFYING SENSITIVE PERIODS FOR OPTIMAL INTERVENTION. TO DETERMINE EARLY RISK AND PROTECTIVE FACTORS, AND RELATED MECHANISMS, TO SERVE AS NOVEL INTERVENTION GROUPS, AND, TO DEVELOP RELIABLE AND ROBUST BIOMARKERS AND ASSESSMENT TOOLS TO PREDICT ILLNESS ONSET, COURSE, AND ACROSS DIVERSE POPULATIONS. TO DEVELOP NOVEL INTERVENTIONS USING A MECHANISM-INFORMED, EXPERIMENTAL THERAPEUTICS APPROACH, AND, TO DEVELOP AND IMPLEMENT MEASUREMENT STRATEGIES TO FACILITATE MECHANISM-BASED INTERVENTION DEVELOPMENT AND TESTING. TO INVESTIGATE PERSONALIZED INTERVENTION STRATEGIES ACROSS DISEASE PROGRESSION AND DEVELOPMENT, AND, TO DEVELOP AND REFINE COMPUTATIONAL APPROACHES AND RESEARCH DESIGNS THAT CAN BE USED TO INFORM AND TEST PERSONALIZED INTERVENTIONS. TO DEVELOP AND TEST APPROACHES FOR ADAPTING, COMBINING, AND SEQUENCING INTERVENTIONS TO ACHIEVE THE GREATEST IMPACT ON THE LIVES AND FUNCTIONING OF PERSONS SEEKING CARE, TO CONDUCT EFFICIENT PRAGMATIC TRIALS THAT EMPLOY NEW TOOLS TO RAPIDLY IDENTIFY, ENGAGE, ASSESS, AND FOLLOW PARTICIPANTS IN THE CONTEXT OF ROUTINE CARE, AND, TO ENHANCE THE PRACTICAL RELEVANCE OF EFFECTIVENESS RESEARCH VIA DEPLOYMENT-FOCUSED, HYBRID, EFFECTIVENESS-IMPLEMENTATION STUDIES. TO EMPLOY ASSESSMENT PLATFORMS WITHIN HEALTHCARE SYSTEMS TO ACCURATELY ASSESS THE DISTRIBUTION AND DETERMINANTS OF MENTAL ILLNESSES AND TO INFORM STRATEGIES FOR IMPROVED SERVICES, TO OPTIMIZE REAL-WORLD DATA COLLECTION SYSTEMS TO IDENTIFY STRATEGIES FOR IMPROVING ACCESS, QUALITY, EFFECTIVENESS, AND CONTINUITY OF MENTAL HEALTH SERVICES, AND, TO COMPARE ALTERNATIVE FINANCING MODELS TO PROMOTE EFFECTIVE AND EFFICIENT CARE FOR INDIVIDUALS WITH SERIOUS EMOTIONAL DISTURBANCES AND SERIOUS MENTAL ILLNESSES. TO STRENGTHEN PARTNERSHIPS WITH KEY STAKEHOLDERS TO DEVELOP AND VALIDATE STRATEGIES FOR IMPLEMENTING, SUSTAINING, AND CONTINUOUSLY IMPROVE EVIDENCE-BASED PRACTICES, TO BUILD MODELS TO SCALE-UP EVIDENCE-BASED PRACTICES FOR USE IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE AND OTHER SETTINGS, AND, TO DEVELOP DECISION-SUPPORT TOOLS AND TECHNOLOGIES THAT INCREASE THE EFFECTIVENESS AND CONTINUOUS IMPROVEMENT OF MENTAL HEALTH INTERVENTIONS IN PUBLIC AND PRIVATE PRIMARY CARE, SPECIALTY CARE, AND OTHER SETTINGS. TO ADAPT, VALIDATE, AND SCALE-UP PROGRAMS CURRENTLY IN USE THAT IMPROVE MENTAL HEALTH SERVICES FOR UNDERSERVED POPULATIONS, TO DEVELOP AND VALIDATE SERVICE DELIVERY MODELS THAT PROVIDE EVIDENCE-BASED CARE FOR INDIVIDUALS THROUGHOUT THE COURSE OF MENTAL ILLNESS, TO DEVELOP AND VALIDATE SYSTEMS-LEVEL STRATEGIES USING TECHNOLOGY AND OTHER APPROACHES, TO IDENTIFY, SUPPORT, AND MONITOR THE EFFECTIVENESS OF EVIDENCE-BASED CARE THROUGHOUT THE COURSE OF ILLNESS, AND, TO DEVELOP AND VALIDATE DECISION-MAKING MODELS THAT BRIDGE MENTAL HEALTH, MEDICAL, AND OTHER CARE SETTINGS TO INTEGRATE THE APPROPRIATE CARE FOR PEOPLE WITH SERIOUS MENTAL ILLNESSES AND COMORBID MEDICAL CONDITIONS.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Pennsylvania United States

State-Wide

HIV Infection of the Central Nervous System (R01 Clinical Trial Not Allowed) (PA-20-149)

Amendment Since initial award the total obligations have increased 393% from $782,443 to $3,855,807.