Contact
Department
Host Pathogen Interaction, Texas Biomedical Research InstituteKulkarni, Smita, Ph.D.
Adjunct Assistant Professor
Personal Statement:
The clinical outcomes of viral infection are highly variable among individuals and are determined by complex interactions between the virus and the host. The majority of the human transcriptome consists of long noncoding RNAs (lncRNAs), which regulate the expression and function of protein-coding genes, cellular functions, and response to infections. How the host lncRNAs impact the replication and pathology of virus infectiona is unknown for most lncRNAs. Through an NIH-funded project, we recently discovered a novel mechanism of regulating HIV co-receptor CCR5 by a lncRNA, CCR5AS, which significantly influences HIV infection and disease outcomes. Multiple reports indicate the role of lncRNA expression may deregulate cellular and immune responses in virus infection. We have designed an in vitro silencing screen to determine the impact of virus-induced lncRNAs on viral replication.
Our studies are revealing lncRNAs that regulate viral replication and type I interferon (IFN-I) response. Our laboratory deciphers the functional role of virus-induced lncRNAs in viral replication and immune response. My laboratory has established all the necessary molecular and cell biology techniques. In addition, we have adapted CRISPR/Cas13d (CasRx) tool to target long noncoding RNAs. CasRx allows precise targeting of RNA independent of structural constraints. We employ CasRx-silencing to determine the functional impact of lncRNAs significantly affecting virus replication. I have broad training and experience in immunogenetics and have extensive experience in human gene regulation through epigenetic mechanisms, regulatory RNAs, and their role in disease (Nature 2011, PNAS 2013, J Immunol 2017, Nat Immunol 2019).
Education
University of Mumbai, India, B.Sc, 1996, Biology
Haffkine Institute, Mumbai, India, M.Sc, 2000, Virology & Immunology
ACTREC, University of Mumbai, India, Ph.D, 2007, Applied Biology
Johns Hopkins Medical Institute, Baltimore, MD, Postdoctoral, 2008
Infectious Diseases, National Cancer Institute, Frederick, MD, Postdoctoral, 2013
Research
Several genetic factors can modulate HIV-1 disease. However, genome-wide association studies (GWAS) across populations have shown that some of the identified disease-associated single nucleotide polymorphisms are in non-coding regions. Due to lack of functional explanation of the observed associations, these host genetic factors cannot be currently utilized as vaccine or drug targets. We are interested in studying non-coding gene variation that modulates HIV-1 disease.
Effect of lncRNA on HIV disease. Less than 3% of the entire transcriptome is protein coding, signifying that non-coding RNAs represent most of the human transcriptome. Long non-coding RNA transcripts, termed lncRNAs (>200bp) have been identified in mammalian genomes by analysis of transcriptomic data, and while thousands of lncRNAs are known, not many of their functions have been identified. The lincRNAs have been implicated in the regulation of many cellular and developmental processes such as imprinting, dosage compensation, cell cycle regulation, pluripotency, retrotransposon silencing, meiotic entry, and telomere lengthening. My lab is interested in the role of lncRNAs in HIV replication and latency.
We have identified polymorphisms in the lncRNA genes that associate with HIV viral load control. These lncRNAs could potentially affect HIV pathogenesis and could represent the first example of a variation in lncRNA expression that affects disease; we are further investigating the function of inter-genic loci that mark diversity in disease outcomes.
Role of alternative 3’UTRs in gene regulation and diseases. Several human genes utilize alternative polyadenylation to generate transcript isoforms with varying lengths of 3’untranslated regions (3’UTR). 3’UTRs encode docking sites for regulatory RNA binding proteins and microRNAs, and thus are major determinants of post-transcriptional gene regulation. Alternative 3’UTR usage is extensively modulated in development, differentiation, proliferation, and neuron activation; alternative 3’UTRs could contribute to both gene expression and protein diversity.
Mutations in polyadenylation signals and other poly(A) cis-elements that lead to changes in gene expression can contribute to the development of human genetic diseases. A dysregulation of alternative 3’UTRs plays a role in cardiac hypertrophy and tumor progression. Manipulation of the length of 3’UTR can alter gene regulation and is considered promising for future therapeutic blocking of angiogenic signals in tumors.
Even though over 70% of human genes contain multiple poly(A) sites and could potentially be subjected to alternative 3’UTR regulation, it is not known what percentage is actually regulated by alternative 3’UTR and whether this results in any biological effects. We are studying alternative 3’UTRs of immune genes that may have an effect on immune response diversity and subsequent outcomes of infectious and autoimmune diseases.