4th International Conference on Neurology and Brain Disorders

September 09-11, 2021

September 09 -11, 2021 | Virtual Event
INBC 2021

Vir Singh

Speaker at Neurology and Brain Disorders 2021 - Vir Singh
Albany College of Pharmacy and Health Sciences, United States
Title : Human Immunodeficiency Virus-1 Tat exerts its neurotoxic effects by downregulating Sonic Hedgehog signaling

Abstract:

HIV-1 can alter the expression of tight junction proteins by downregulating Sonic hedgehog (Shh) signaling, thereby disrupting BBB integrity. In this study, we employed a conditional, CNS specific, transgenic murine model to investigate if Tat, a known neurotoxic HIV protein, is responsible for dysregulation of Shh signaling. Results indicate that Tat+ mice exhibit reduced expression of Shh, Gli-1 and Smoothened proteins. Tat+ mice also express lower levels of tight junction protein Claudin-5 and higher levels of adhesion protein Vcam-1. As a result of these BBB alterations significantly higher numbers of leukocytes infiltrate into the CNS of Tat+ mice as compared to Tat- mice. Administration of Smoothened agonist (SAG), a Shh mimetic, significantly reduced the number of brain-infiltrating leukocytes (BILs) in Tat+ mice. Further, our in vitro experiments using human brain microvascular endothelial cells suggest that pharmacological induction of Shh signaling can rescue detrimental effects of Tat on endothelial function by inducing the expression of junctional proteins and by decreasing the levels of inflammatory cytokines/chemokines such as CCL2, IL-1? and IL-6. Overall, this study identifies a novel mechanism by which HIV-1 Tat exerts its neurotoxic effects as well as underscores the neuroprotective role of Shh signaling in adult brain. Findings from this study can be used to devise potential therapeutic approaches to alleviate HIV associated neuropathogenesis.

Biography:

Dr. Singh is a virologist with special interest in molecular mechanisms that are involved in HIV replication and neuropathogenesis. He received his PhD in Biotechnology from Savitribai Phule Pune University (India) in 2009. Subsequently, during his postdoctoral training at Roswell Park Cancer Institute (RPCI), he studied the phenomenon of genomic imprinting and investigated the mechanism of establishment of maternal methylation at KvDMR1 Imprinting control region (ICR). This study proposed a potential mechanism of loss of methylation at KvDMR1 that results in a developmental disorder known as Beckwith Wiedemann syndrome. Further, he moved to University of Rochester Medical Center, Rochester, NY, where he worked for over 7 years, first as a postdoc and eventually promoted to Research Assistant Professor. During this time, he investigated the molecular mechanisms involved in HIV associated neurological disorder. Currently, Dr. Singh is employed as Assistant Professor of Microbiology at Albany College of Pharmacy and Health Sciences. Collectively, he has acquired an extensively diverse experience in investigating the molecular mechanisms implicated in various diseases including anemia, developmental growth syndromes predisposed to cancer, and HIV pathogenesis. As an independent investigator, Dr. Singh’s research interests include understanding the basic molecular mechanisms involved in- i) HIV associated neurological disorder, ii) HIV latency, and iii) Viral infection induced developmental defects.

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