— College of Medicine — Department of Pharmacology and Experimental Neuroscience — Faculty — Susmita Sil, PhD — Laboratory of Susmita Sil, PhD

Laboratory of Susmita Sil, PhD

Research interest:

My primary goal is to investigate the effects of different drugs of abuse and HIV on the mechanisms involved in glial cells mediated neurodegeneration involving cellular crosstalk by extracellular vesicles. My long-term research goals are to investigate the different molecular mechanisms leading to neuronal injury and dementia in drug addicts, HIV patients as well as other neurodegenerative diseases. Using RNA based therapies I would like to target the upstream components involved in neuronal injury in these disease condition(s).

Ongoing projects:

Alzheimer’s like pathology as a co-morbidity of HIV: Role of astrocytes

Increased life expectancy of HIV+ patients in the current era of effective treatment is unfortunately accompanied with the continued prevalence of HIV-associated neurological disorders and risk of age-associated comorbidities such as Alzheimer’s Disease (AD). Interestingly, there are reports implicating HIV-1 Tat-mediated production of the toxic neuronal amyloid protein and the interaction of the two, further resulting in enhanced neurotoxicity. In the current project, I sought to assess the contribution of other non-neuronal cells such as the astrocytes in Tat-mediated amyloidosis. Findings showed that astrocytes can produce amyloids in presence of HIV protein Tat, HIV/ SIV, and HIF-1α-lncRNA BACE1-AS complex is associated with this process of astrocytic amyloidosis and can be targeted to develop adjunctive therapies for HAND-associated comorbidity of Alzheimer’s like pathology.

Role of extracellular vesicles in disease pathogenesis

Extracellular vesicles (EVs) have become the focus of rising interest because of their numerous functions in physiology and pathology. Cells release heterogeneous vesicles of different sizes and intracellular origins, including small EVs formed inside endosomal compartments (i.e., exosomes) and EVs of various sizes budding from the plasma membrane. Based on the existing literature on the role of brain and serum-derived extracellular vesicles (EVs) in seeding of the toxic amyloid forms to various sites in the CNS and the periphery, we hypothesized that Tat exposed astrocytes could also mediate amyloidosis that could be propagated via EVs, leading, in turn, to further potentiation of pathogenesis of HAND. We are screening for various amyloid forms in the brains of HIV/ SIV+ subjects. We are isolating and characterizing the neuron, microglia & astrocyte derived EVs from brain and serum invivo via differential ultracentrifugation, characterization by Zetaview, Atomic force microscopy, Electron microscopy, and immunoblot analysis. We are assessing for the presence of neurotoxic proteins, inflammatory components & ageing cargoes in the EVs. These findings will give us information about the role of specific EVs in disease progression and as biomarkers.

Adeno associated virus (AAV) mediated genetic manipulation

AAVs are emerging as valuable genetic manipulation vehicle, due to efficient invivo infectivity, non-pathogenicity, widespread tissue tropism, rare genomic integration & their ability to infect & persist in cells for a long period. For this we chose to resort to AAVs as delivery vectors since they have been shown to be safe & most effective gene delivery vehicles for transducing broad range of cell types. These vectors can be engineered to target specific cell types. We are engineering AAVs with CNS cell specific targeting to overexpress or inhibit non-coding RNAs to assess their function in HIV-associated neurocognitive disorder (HAND) & substance use-disorders.