DP1DA056018

Single Chromatin Fiber Sequencing and Longitudinal Epigenomic Profiling in HIV+ Brain Cells Exposed to Narcotic and Stimulant - HIV-Associated Neurocognitive Disorders Persist in the Era of Combination Antiretroviral Therapy (CART) while HIV Latency, and Cell-Specific Expression of HIV Transcript in Human CNS remains incompletely understood.

There is a high prevalence of HIV-associated neurologic disease and increasing recognition of CNS viral escape in people stably suppressed with CART, often further complicated by the co-registered epidemic of substance use disorders (SUD) in people living with HIV/AIDS (PLWHA), as SUD also have a profound impact on CNS function.

Ongoing work in our laboratory is providing first assessments of cell-type specific HIV 'molecular signatures', including genome integration patterns and alterations on the level of the transcriptome and epigenome in reward- and addiction circuitry of the human postmortem brain. However, like virtually all other genomic approaches in the field, our ongoing studies face two massive limitations:

(A) Exclusively cross-sectional design, limited to a snapshot of genome organization and function at a single time point – the time of death of the brain donor. The very same limitation obviously applies to cell culture and animals. This is extremely unfortunate as such types of endpoint epigenome and transcriptome mappings in infected and non-infected brain cells cannot inform about cell-specific chromatin status during earlier periods in the life of the cell.

(B) Conventional brain neurogenomics is thus far limited to short read sequencing of chromatin, typically extending 150 base pairs or less per read. However, it would be much more informative to profile, at base pair resolution, epigenomic chromatin landscapes across a wider window encompassing full-length retroviral insertion sites, which are two orders of magnitude above current read length.

In this avant-garde project, we will, for the first time, for each brain, embark on retrospective/longitudinal epigenomic profiling, using a xenograft model well established in the HIV field, together with genetically engineered human iPSC-derived hematopoietic progenitor cells (HPC). We will, for the first time, embark on the longitudinal epigenomic tagging of single chromatin fibers and explore dynamic changes and even reversibility (or progressive deterioration) of the epigenomic dysregulation in HIV infected myeloid-derived cells residing in brain and blood.

Icahn School Of Medicine At Mount Sinai

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]

New York, New York 100296504 United States

Single Zip Code

NIDA Avant-Garde Award Program for HIV/AIDS and Substance Use Disorder Research (DP1, Clinical Trial Optional) (PAR-20-221)

Amendment Since initial award the total obligations have increased 300% from $1,183,000 to $4,732,000.