Faculty in MRDG who would be interested in PhD students this year are as follows:
Receptor guanylyl cyclase C: gut biology and gut physiology
Receptor guanylyl cyclase C (GC-C) is a major receptor in intestinal epithelial cells that regulates a myriad of function including fluid and ion homeostasis, intestinal cell proliferation and regulating infection by gut pathogens (1, 2) . While our earlier work focused on understanding aspects of the biochemical properties of this receptor and its domain organization, we have now begun studies where we are developing mouse models that mimic mutations that we have characterized earlier (3,4), and are seen in human patients with congenital secretory diarrhoea. Our efforts lie in providing a molecular understanding of the pathophysiology seen in these patients through the use of a number of techniques that include next generation sequencing, proteomics and gut organoid cultures. We will expand on these studies using novel transgenic mice that we have obtained, and will also look to identifying modulators of receptor activity that could provide therapeutic approaches in the future.
Our research interests in a broad sense lie in the area of Human Molecular Genetics and Cancer Biology. Currently, we are looking for a motivated student to work on any one of the following two projects.
Project 1: Role of microRNAs in oral cancer: In India, oral cancer is the leading cancer in males and the third most common malignancy in females. However, in spite of many advances in its treatment, the 5-year survival rate for oral cancer has remained unchanged during the last few decades. It is thus imperative to identify novel therapeutic targets for oral cancer. Recent studies have shown deregulation of microRNA expression and the contribution of microRNAs to the multi-step process of tumorigenesis, either as oncogenes or tumor suppressor genes. In recent years, microRNAs have been used as therapeutic targets in several cancers. Given this background, we wish to explore, identify and exploit the role of microRNAs in oral cancer with an aim to use them as therapeutic targets, using a preclinical xenograft nude mouse model.
Project 2: Identification of novel transcriptional targets of tumor suppressor TSC2: Mutations in the TSC2 gene cause an autosomal dominant genetic disorder, Tuberous Sclerosis Complex (TSC), characterized by hamartomas (benign tumor-like outgrowths) in affected organs such as the brain, eyes, skin, lungs, kidneys etc. TSC2 protein interacts with TSC1 and forms the TSC1/TSC2 complex. Mutations in the TSC1 gene also cause TSC. The TSC1/TSC2 complex negatively regulates mTORC1 in the PI3K-AKT-TSC1/TSC2-mTOR (insulin signaling) pathway, and in turn regulates cell proliferation. Both genes function as tumor suppressors. TSC1 localizes to the cytoplasm, whereas TSC2 shows nuclear as well as cytoplasmic localization. Using gene expression profiling of TSC2 overexpressing cells, luciferase reporter assay, ChIP and EMSA techniques, we have recently shown for the first time that TSC2 also functions as a transcription factor and regulates the transcription of Epiregulin, a ligand for EGFR. We plan to further explore and identify other genes (protein coding and microRNAs), which are transcriptionally regulated by TSC2 and their role and utility as therapeutic targets in oral cancer.
Currently, we are looking for a motivated student to work on the following project. The student will be co-supervised by both the faculty.
Risk and protective genetic factors for neurodegenerative diseases & interaction using an integrated genome wide approach: In the coming years, neurodegenerative disorders, especially dementia and stroke will pose as one of the greatest socioeconomic and intellectual challenges for India. Under this project, students will be exposed to the latest cutting edge genetic tools and techniques including next generation sequencing and genome wide approaches for neurodegenerative disorders. This will give them the opportunity to explore the huge genetic diversity of India, leading to the identification of novel genes, biological pathways and mechanisms to better understand these diseases and design therapeutic interventions. Students will have the opportunity to work both in the lab and in the community, and get exposed to both “wet-experimental” and “dry-computational” lab techniques.
Primarily our group is interested on understanding the molecular and genetic basis of myopathies and neurodegenerative disorders, using the genetically amenable model organisms, Drosophila – Fruit fly and Danio rerio – Zebrafish. We also use both the model systems for dissecting muscle and neural related Immunity responses, Drug screening, Functional genomics and Biomechanics studies. Our long term goals include providing therapeutic solutions and developing new diagnostic tools for protein aggregate myopathies, Dystrophies, neurodegenerative diseases and age-related disorders.
Cancer and stem cells:
A fundamental property of cancer cells is uncontrolled growth. Yet, very few cancer cells form colonies in soft-agar assays in vitro or contribute to tumor initiation in mice models. Such minority cell population, that has the ability to both self-renew to give rise to their own kind, as well as generate the bulk of tumor cells, has been termed as cancer stem cells (CSCs). The CSCs are also inherently drug resistant, thus contributing to treatment failure and disease relapse. The developmental process of epithelial-mesenchymal transition (EMT) is associated with the generation of stem-like properties and drug resistance in cancer cells. The main interest of our laboratory is to understand the underlying mechanisms that contribute to the properties of stemness, EMT and drug resistance – the evil axis in cancer therapeutics. Recent work in our laboratory has identified AMP-activated protein kinase (AMPK) as a stress kinase that is activated under matrix-detachment and confers anchorage-independent survival – a key requirement for cancer metastasis. Interestingly, AMPK is also associated with maintaining cancer stemness and promotes EMT. The key questions being addressed currently in the lab are:
1) What are the signaling mechanisms downstream of AMPK activation that promote survival in matrix-deprived cancer cells?
2) How does AMPK confer cancer cells with properties of stemness and drug resistance?
3) Can we better understand the ‘state’ of matrix-deprived cancer cells by integrating transcriptomics and proteomics data to identify emergent networks?
To address these querries, we propose to use in vitro cell biological assays using cancer cell lines, animal models (Mouse and Drosophila), human patient samples, and high-throughput data collection and analysis.
Potential projects in SaINI lab includes physiological analysis of signaling crosstalk in M. tuberculosis; aging and inflammation and effect of aging on infection. Please contact SaINI lab for more details.
Developmental Epigenetics; X-chromosome inactivation and reactivation; Long non-coding RNA; Chromatin modifiers
Emerging evidence implicates that epigenetics plays a major role in developmental processes. However, often dysregulation of epigenetic processes leads to different human diseases such as cancer. Unlike irreversible mutations in DNA, epigenetic modifications are reversible. This inherent plasticity makes epigenetic changes associated with human diseases potentially amenable to manipulation via therapeutic intervention. Therefore, understanding of epigenetic regulation is crucial for our comprehension of the alterations that can lead to disease. However, much about the mechanistic aspects of epigenetic regulation remains to be understood. Our research strives to further the understanding of mechanism of epigenetic regulation through the study of X-chromosome inactivation and reactivation during transition of pluripotent sub states using mouse embryo and stem cells.