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Principal Investigator: Laura Cheney
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $194,400
Funding agency: National Institute of Mental Health
Project Summary/Abstract
This proposal presents a 4 year research career development program focused on the study of
macroautophagy (autophagy) in the context of HIV associated neurocognitive disorders (HAND) to increase
the understanding of HAND pathogenesis with the goal of identifying targets for treatment of HAND. The
candidate is currently an Instructor of Infectious Diseases and of Pathology at Montefiore Medical
Center/Albert Einstein College of Medicine. The proposal builds on the candidate’s previous HIV research and
clinical experiences by integrating two new domains of expertise, overseen by her mentors, Dr. Berman and
Dr. Cuervo. The proposed experiments and didactic work will provide Dr. Cheney with the skill sets to enable
her transition to independence as a Principal Investigator at the crossroads of neuroHIV and macroautophagy.
A significant number of people with HIV (PWH) develop HAND despite control of viremia with antiretroviral
therapy (ART). Efforts to treat HAND are hindered by an incomplete understanding of the factors underlying its
development. Data suggest that dysregulated autophagy may contribute to HAND, but much remains to be
understood, specifically in astrocytes. It is essential to maintain astrocyte homeostasis because they are major
support cells of the brain, performing many vital functions for the CNS. As astrocytes rely on autophagy for
homeostasis, it is particularly important to understand dysregulated astrocyte autophagy as it may contribute to
HAND. The foundation for this proposal is based on our published data demonstrating an inhibitory effect on
autophagy in primary human astrocytes resulting from treatment with a commonly prescribed regimen of
Tenofovir, Emtricitabine and Raltegravir (ART). The aims of this proposal are to: 1. Characterize ART induced
changes in autophagy in human astrocytes, 2. Characterize selective autophagy in human astrocytes treated
with ART, and 3. Define changes in astrocyte-specific functions as a result of ART treatment, and correlate
with changes in autophagy. These aims will expand the understanding of HAND development in PWH in the
ART era, with the ultimate objective of identifying therapeutic targets with which to mitigate HAND.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Anti-Retroviral Agents><Astrocytes><Astrocytus><Astroglia><Autophagocytosis><Autopsy><Autoregulation><Brain><Brain Nervous System><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Communicable Diseases><Confocal Microscopy><Data><Degenerative Neurologic Disorders><Development><Drugs><Dysfunction><ELISA><Employment><Encephalon><Enzyme-Linked Immunosorbent Assay><Exposure to><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Foundations><Functional disorder><Genus Hippocampus><Glutamates><Goals><HIV><HIV 1 associated neurocognitive disorder><HIV Infections><HIV associated neurocognitive deficit><HIV associated neurocognitive impairment><HIV associated neurological disease><HIV associated neurological disorder><HIV induced neurocognitive deficit><HIV induced neurocognitive impairment><HIV neurocognitive impairment><HIV-1 associated neurocognitive deficit><HIV-1 associated neurocognitive disorder><HIV-1 associated neurocognitive impairment><HIV-associated neurocognitive disorder><HTLV-III Infections><HTLV-III-LAV Infections><Homeostasis><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immunoblotting><Immunofluorescence><Immunofluorescence Immunologic><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><L-Glutamate><LAV-HTLV-III><Learning><Lymphadenopathy-Associated Virus><Measures><Mediating><Medical center><Medication><Medicine><Membrane Potentials><Mentors><Microscopy><Mitochondria><Modeling><Modern Man><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocognitive Impairment in HIV><Neurocognitive Impairment in HIV-1><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuropathogenesis><Non-Polyadenylated RNA><Pathogenesis><Pathogenicity><Pathology><Persons><Pharmaceutical Preparations><Physiological Homeostasis><Physiopathology><Principal Investigator><Process><Production><Program Development><Protein Cleavage><Proteins><Proteolysis><Proteomics><Publishing><QOL><Quality Control><Quality of life><Quantitative RTPCR><Quantitative Reverse Transcriptase PCR><RNA><RNA Gene Products><Receptor Protein><Regimen><Reporter><Research><Respiration><Resting Potentials><Ribonucleic Acid><Role><Seahorse><Specificity><Stimulus><Subcellular Process><Supporting Cell><Techniques><Tenofovir><Toxic effect><Toxicities><Transmembrane Potentials><Transmission Electron Microscopy><Viread><Viremia><Virus-HIV><Western Blotting><Western Immunoblotting><Work><anti-retroviral><antiretroviral therapy><antiretroviral treatment><astrocytic glia><autophagy><beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine><brain cell><brain tissue><career development><cell type><co-morbid><co-morbidity><college><collegiate><comorbidity><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><develop therapy><developmental><drug/agent><emtricitabine><enzyme linked immunoassay><experience><experiment><experimental research><experimental study><experiments><extracellular><flow cytophotometry><glutamatergic><inhibition of autophagy><innovate><innovation><innovative><instructor><intervention development><knock-down><knockdown><light microscopy><mitochondrial><mitochondrial autophagy><mortality><natural aging><necropsy><neuro-AIDS><neuro-HIV><neuroAIDS><neuroHIV><neurodegenerative illness><normal aging><normative aging><novel><overexpress><overexpression><pathophysiology><pharmacologic><postmortem><prevent><preventing><protein blotting><qRTPCR><receptor><respiratory mechanism><response><skills><social role><therapeutic target><therapy development><tool><treatment development><uptake><viraemia><viral sepsis><virusemia>