Scientific Interest
Genomics | Multiomics | Precision Medicine | Pathogen Genomics
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Non-coding RNA mediated regulation of vascular disease using multiomics approaches
Development of the vascular system is a tightly regulated multistage process and zebrafish has been established as an excellent model for studying human vascular biology and disease. Importantly, the genetic programs that regulate the development of these important processes are conserved through evolution. Multiple protein coding genes and several non-protein coding genes have been known to be involved in the development and maintenance of the vascular system.
We documented the dynamic expression landscape of Long non-coding RNAs (lncRNAs) in adult zebrafish and identified over 400 novel lncRNAs. LncRNAs with specific expression in the cardiovascular tissues of zebrafish were identified (Kaushik et al., 2013, Ramcharan et al., 2016). Work from our lab has established the biological role of several Non-Coding RNAs (ncRNA).
Long non-coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. We investigated the role of a novel vascular endothelial-associated lncRNA (VEAL2) in regulating endothelial permeability. Based on experimental evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a previously unknown VEAL2 lncRNA-mediated regulation of Protein kinase C beta (PRKCB), for modulating junctional dynamics and maintenance of endothelial permeability. Protein kinase C beta (PRKCB) is known to promote vascular permeability, and its hyper-activation has been linked to diabetic retinopathy.
Elevation in expression levels of VEAL2 in blood of patients with diabetic retinopathy poses a potential application as a biomarker for aggravating microvascular complications. Work form our lab puts forth VEAL2 as a potential candidate for lncRNA-mediated inhibition of PRKCB2 in pathological conditions with excessive endothelial permeability (Sehgal et al., 2021, EMBO J- https://pubmed.ncbi.nlm.nih.gov/34180064/).
Genomics for Public Health in India
India encompasses more than 17% of the world population with extensive genetic diversity, but is under-represented in the global sequencing datasets. Our lab has been actively working towards filling this gap. In the year 2009 we undertook sequencing of the first personal human genomes from India (Patowary et al., 2012), Sri Lanka and Malaysia (Salleh et al., 2013). This was followed by sequencing of centenarian genomes from India (Hariprakash et al., 2018).
The IndiGen programme (https://indigen.igib.in/) aims to undertake whole genome sequencing of thousands of individuals representing diverse ethnic groups from India. The objective is to enable genetic epidemiology and develop public health technologies applications using population genome data. We sequenced and analyzed the whole genomes of 1029 healthy Indian individuals under the pilot phase of the ‘IndiGen’ program. A compendium of 55,898,122 single allelic genetic variants from geographically distinct Indian genomes were documented. These variants were systematically annotated and can be accessed through a browsable online database named as ‘IndiGenomes’ http://clingen.igib.res.in/indigen/.
The IndiGenomes database will help clinicians and researchers in exploring the genetic component underlying medical conditions (Jain and Bhoyar et al., 2021, Nucleic Acid Res https://pubmed.ncbi.nlm.nih.gov/33095885/)
Genomics of Rare Genetic Diseases
Genome sequencing has been increasingly adapted for diagnosis of genetic diseases. It is also anticipated that genome-guided therapeutic decisions would find its place in optimizing therapeutic interventions and minimizing adverse events. One of the major applications of such genomic technologies in the clinical settings could focus on the identification and annotation of variants associated with Rare Genetic Diseases.
Rare genetic diseases are becoming a public health concern in India because a large population size of close to a billion people would essentially translate to a huge disease burden for even the rarest of the rare diseases. Genomics-based approaches have been demonstrated to accelerate the diagnosis of rare genetic diseases and reduce the socio-economic burden. The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN) stands for providing genomic solutions for rare diseases in India. The consortium aims to establish a unique collaborative framework in health care planning, implementation, and delivery in the specific area of rare genetic diseases. It is a nation-wide collaborative research initiative catering to rare diseases across multiple cohorts, with over 280 clinician/scientist collaborators across 60 major medical/research centers. Within the GUaRDIAN framework, clinicians refer rare disease patients, generate whole genome or exome datasets followed by computational analysis of the data for identifying the causal pathogenic variations. The outcomes of GUaRDIAN are being translated as community services through a suitable platform providing low-cost diagnostic assays in India. Read more about GUaRDIAN https://pubmed.ncbi.nlm.nih.gov/31554517/
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