Cervical cancer is one of the leading causes of cancer related deaths among Indian women. One of the major risk factors, which accounts for 99.7%, cases of the cervical cancer is persistent infection with a sexually transmitted, high risk Human Papilloma Virus (HPV). It has been found that E6 and E7, two oncoproteins encoded by HPV, deregulates p53 and pRb and promotes cervical cancer in th e hosts. It is seen that non-coding RNAs (miRNA and lnc-RNAs) play differential roles in the normal cellular physiology and molecular pathogenesis of several diseases, including cancer. My aim is to explore the involvement of miRNAs in HPV16 driven cervical cancers specifically associated with viral oncoprotein E7, the interaction or the crosstalk of lncRNA with cellular miRNAs, under the influence of E7 expression and to investigate how they influence HPV16 related CaCx pathogenesis.
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Cervical cancer is one of the leading causes of cancer related deaths among Indian women. Persistent infection with oncogenic Human Papillomavirus (HPV) is the major etiology of the disease. Expression of the viral oncoproteins E6 and E7 are critical for malignant transformation of the host cells and is mediated through the interaction with other host encoded molecules. E6 regulates the decay of tumor suppressor p53, while E7 interacts with pRb leading to cellular transformation and neoplastic progression of the cervical epithelial cells. My aim is to identify the intrinsic HPV 16 E7 mediated pathways relevant for cervical cancer pathogenesis, focusing majorly on the immune pathway molecules and correlate such intrinsic host molecular factors with some of the extrinsic phenomena of tumor immune microenvironment in cervical cancer pathogenesis. Read less
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A number of GWAS studies conducted in 2009 on HCV (hepatitis C virus) showed that polymorphisms/variants in the interferon-lambda (IFNL) locus affect the HCV disease outcomes. Following this, in 2013, a new type III IFN, Interferon lambda-4 (IFN-λ4) was discovered. This gene is expressed due to the presence of the ΔG allele at the dinucleotide polymorphism rs368234815. Even though IFN-λ4 has p otent antiviral effects, its presence is associated with poor viral clearance in HCV-infected patients. Further studies have shown that polymorphisms, especially on IFNL4 and IFNL3, are intricately associated with many infectious and inflammatory diseases, such as fibrosis, COPD, asthma, thyroid, SLE, and certain cancers. Only a subset of individuals in our population (~>50% of Indians) can express a functional IFN-λ4. Even though strong association can be seen with IFNL4 polymorphisms with disease phenotypes in genetic studies, functional evidence for its role in such conditions has not been forthcoming. This has led to questions on the significance of IFN-λ4 in such studies at the same time favouring a role for the well-studied and more active IFN-λ3 in deciding some of the phenotypes. Healthy individuals can be good models to study the genetic and the consequent functional effects of IFN-λ3 or IFN-λ4 that may help us to understand the associated disease phenotypes better. I am interested in addressing the fundamental question of whether IFN-λ3 or IFN-λ4 or both could have functions in deciding the antiviral states in healthy individuals. I use an epidemiological study design to address this question. My work has the potential to decisively solve IFNL locus functional variant conundrum. Read less
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Period of gestation being an important determinant of infant’s health, adverse live birth outcomes are major public health concerns of global importance.Complications from preterm birth, which is defined as any live birth before 37 completed weeks of gestation, is the leading cause of mortality of children below 5 years. Interplay between environment and underlying genomics of both the mo ther and the fetus results in the preterm birth outcome. To combat the global health burden, early detection of the women having higher risk for delivering preterm is highly crucial which will help to provide personalized medical care to them. Since genomic markers have the potential to identify the high-risk women even to prior to pregnancy, so I intend to study the maternal genetic influences on preterm birth.
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Birth outcome is an important determinant of an infant’s survival and health even during adulthood. Identifying the complex physiological and molecular pathways involved in modulation of pregnancy outcomes is thus of paramount importance for understanding and developing strategies to reduce adverse birth outcomes like preterm birth (PTB). Genetic markers alone may not provide sufficient i nsights into these processes. Epidemiologic observations, mostly from neonatal genomes, suggest probable role of epigenetic disruptions in enhancement of risk of PTB. However, very limited information is available on the role of maternal epigenome in PTB till date. My goal is to study the temporal variations in maternal DNA methylation landscape that occur during pregnancy and identify those that are associated with adverse outcomes.
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Identification of causal variants together with the potential mechanism contributing to differential disease risk among individuals can offer most critical insights into the proper understanding of complex diseases. So far, Genome-Wide Association Studies have been remarkably successful in identifying genetic variants associated with various complex diseases. However, the interpretation of GWAS variants in terms of causality and the perception regarding the role played by these variants in the etiology of complex diseases have remained significantly ambiguous. Hence, we require robust statistical methods to efficiently integrate epigenomic and transcriptomic signatures and the intricate network of gene-regulation in relevant tissues along with functional annotations, pathways, and other evidence from publicly available databases. My primary interest lies in developing statistical methods for integrative analysis of multi-omics data to systematically identify causal variants within an associated region and to elucidate the causal mechanism through which they act. Methods developed will facilitate interpretation of complex disease associated loci not only to infer genetic causality through the epigenomic, transcriptomic and functional landscape in relevant tissues but also to highlight the upstream genes, pathways directly modulated by these genetic variants and consequent downstream changes.
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Primary angle closure glaucoma (PACG) is one of the leading causes of blindness worldwide with a complex genetic etiology. Several anatomical factors like shallow anterior chamber depth, increased lens thickness, narrow iridocorneal angle etc are involved in the pathogenesis of PACG which could raise intraocular pressure followed by optic neuropathy and subsequent blindness. In India, ~30% peoples show narrow angle but 0.5-1% people actually develop PACG. To exclude heterogeneity, we conducted genome-wide association study (GWAS) between older (age ≥60 years) anatomically suspects (PACS) showing narrow angle <15> Read less
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Oral cancer is the most common cancer among Indian men. In spite of many therapeutic advancements, there has been no significant improvement in the survival outcome of head and neck squamous cell carcinoma. Five year survival rate in advanced stage carcinoma is only 27% & it has high chance of relapse. Recently it is known that tumor microenvironment and stromal components (e.g- fibroblas ts, immune cells, endothelial cells), are as important as genetic mutations and play critical role in cancer development. Tumor contains different subpopulations in terms of mutations and make tumor heterogeneous. These subpopulations may differ in genetic, epigenetic level resulting in variation of the gene expression and protein function. However the reciprocal interaction between cancer cell and stromal component have not been studied in oral cancer. Therefore I am interested in finding the interaction between heterogeneous tumor and its microenvironment. By understanding the cross-talk and reciprocal interaction between tumor cells and stromal components, we can predict novel target against tumor-stromal interaction.
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Breast cancer is one of the most common cancers and the second most leading of cancer death in women. Breast cancer is hormone dependent tumor and estrogen is known to play a major role in the initiation and progression of this cancer. Endocrine therapy is the best therapy for breast cancer. But resistance to endocrine therapy is common. Previous studies account for only 40% of such mechani sms. The aim of my research is to discover newer mechanism using genomics and epigenomics tools to identify novel candidates to combat endocrine resistance.
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Among the recently discovered Type–III interferon family, IFN-λ4 (IFNL4) is thenewest member. I am interested in characterizing the naturally occurring variants of IFNL4 gene for their effect on IFN-λ4’s function and their significance in different human diseases. IFNL4 gene transcription is known to generate several different splice variants. I am also interested to understand if any of the genetic variants within the body of IFNL4 are important in generation of these splice variants.
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