R01DA054534

A Dual Chimera Human Astroglial-Microglial Model of HIV and HAND - Abstract

Synaptic failure is an important feature of HIV infection of the brain, and a likely key contributor to HIV-associated neurocognitive disorders (HAND). Yet current animal models have proven of limited utility in defining the mechanisms of this process, in part because of the species-specific nature of HIV infection, but also because of the greater complexity of human astrocytes relative to those of mice.

To address this issue, we will utilize mice chimeric for both human microglia and human astrocytes, to assess the effects of HIV infection on central neurons. To that end, we will engraft mice with both human glial progenitor cells (HGPCs) and microglia, each derived from embryonic stem cells (HESCs). We have established the methods of generating these human glial chimeras, by the neonatal implantation of HGPCs, which outcompete and ultimately replace the host mouse GPCs, yielding adult chimeras broadly colonized with human astroglia. This process is especially robust in the neostriatum, allowing the glial humanization of regions critically involved in striatal reward and addiction circuits.

We have recently extended this approach to include chimerization with HESC-derived microglia, paired with the use of CSF1R null mice lacking host microglia, crossed to NSG SGM3 mice to allow the stable xenograft of HGPCs. The mice are thus chimeric for HGPC-derived astrocytes as well as microglia, in a T- and B-cell deficient background that allows the effects of glial HIV infection on neurons to be isolated, following intracerebral inoculation with HIV-infected microglia.

These chimeric human astroglial-microglial (CHAM) mice are especially attractive, since they incorporate the hominid-specific features of human astroglia, which are themselves key components of central synapses. Using this model, we will test the postulate that astrocytes become both structurally and functionally impaired by microglial HIV infection, resulting in the loss of synaptic engagement by affected astrocytes, with consequent dendritic involution and network disruption.

By infecting CHAM mice with HIV, and using rabies viral-EGFP to trace striatal dendrites, we will assess the effects of astrocytic HIV infection on the dendritic architecture and synaptic structure of resident medium spiny neurons. In parallel, we will study the effects in CHAM mice of HIV infection complicated by methamphetamine use – a common and disabling comorbidity that suppresses dopaminergic input to the striatum – focusing on the structural and transcriptional responses of human glia to the combination of infection and addiction, as well as on the behavioral effects of that combination.

To that end, we will use single-cell RNA-Seq to assess the changes in gene expression by human astrocytes and their partnered mouse neurons caused by HIV infection, both alone and together with chronic methamphetamine use, to identify those changes that contribute to the striatal synaptic disruption and behavioral pathology of these mice.

Our goal is to test the hypothesis that the HIV-infected striatum, by virtue of astrocytic fiber disengagement from dopaminergic synapses in particular, is especially vulnerable to the effects of amphetamine abuse, while defining the transcriptional basis for the glial pathology underlying that vulnerability.

University Of Rochester

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Rochester, New York 14642 United States

Single Zip Code

Using Human Cell Animal Chimera Brains to Study HIV Latency and Pathology R01 - Clinical Trials Not Allowed (RFA-DA-21-026)

Amendment Since initial award the total obligations have increased 413% from $608,883 to $3,125,946.