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Current Research interests The innate properties of macrophages play an important role in dictating subsequent adaptive immune phenotypes like T helper type 1 (Th1) or Th2 which are important for developing protective immunity against various pathogens. The activation of macrophage leads to production of a wide range of inducible gene products that are essential in developing innate and subsequent acquired immunity. Our research interests focus on how these gene products are modulated during various patho-physiological conditions leading to establishment of diseased states. In particular, we are looking at the molecular `cross talks’ between various cytokines and effector molecules in activated macrophages during tuberculosis, cancer and oxidative stress. Understanding these events is likely to help us in designing better therapeutics like immunotherapy. For this we are using a multidisciplinary approach including cell biology, molecular and cellular immunology and molecular biology.
Ongoing Research and Future Program In general, our laboratory research focus on intracellular signaling pathways and transcriptional control of cytokines in activated macrophages. These projects are part of the research programs that aim to understand how the Mycobacterium tuberculosis bacteria interfere with the macrophage-signaling cascades to down-regulate its anti-mycobacterial immune responses. 1. FUNCTIONAL ANALYSIS OF M. Tuberculosis PROTEINS INTERACTING WITH MACROPHAGE SIGNAL TRANSDUCTION PATHWAYS : Principal Investigator : Dr. Sangita Mukhopadhyay
Tuberculosis (TB) is declared a global emergency by the WHO, the first disease to be so designated which kills about 3 million people a year. The bacillus Mycobacterium tuberculosis remained the leading cause of mortality in the world, even when we are entering into the new millennium of technical and medical excellence. An extremely resilient cell wall, very slow growth, highly contagious nature and a number of cunning strategies adopted by the pathogen to evade host immune attack make it one of the least tractable organism to work with. The rapid spread of tuberculosis in AIDS patients and emergence of multidrug resistant strains renders the situation still grave. The bacterium has a very sophisticated signal transduction systems and potentialities to adapt into a variety of hostile environments. There have been extensive attempts worldwide to identify the mycobacterial components that have an important role in the establishment of the infection. But till date only little information is available regarding the molecular basis of mycobacterial virulence. Development of vaccines is getting hampered because of our insufficient knowledge regarding the host-bacilli interactions and molecular basis of pathogen invasion. Identification and characterization of the set of genes expressed by the M. tuberculosis bacilli during interaction with the host cells will help to increase our understanding of pathogenic mechanisms that result in disease and may provide insights into potential vaccine strategies and novel drug targets. The macrophage mediates the first line of defense in the host. The M. tuberculosis bacilli play various strategies to suppress the macrophage-innate effector and APC (antigen presenting cell) functions and use the host's defense weapon as its comfortable home. In various projects supported by Indian Council of Medical Research (ICMR), Govt. of India, Department of Biotechnology (DBT), Govt. of India, and Department of Science and Technology (DST), Govt. of India, we are approaching to identify and characterize the mycobacterial ORFs/proteins that enable the bacilli to survive and multiply within the macrophages. We also approach to identify the down-stream signal transduction pathways in macrophages modulated during TB infection, which is important to understand how the bacterium invades the macrophage cells successfully. This work will provide new insights about the detrimental endogenous immune responses triggered by the mycobacterium bacilli and shed some light on the molecular basis of pathogenesis of this dreadful pathogen. Current approaches :
We intend to focus on i) identification of the mycobacterial virulent factors important for establishment of disease within the macrophage, ii) the host-pathogen interaction and the iii) implementation of immunotherapeutic approaches for anti-tuberculosis immunity.
2. STRESS MEDIATED ALTERATIONS IN IMMUNE RESPONSES: Principal Investigator : Dr. Sangita Mukhopadhyay
Project Summary Reactive oxygen species or ROS are oxygen free radicals and their by-products that cause oxidative damage of cellular components like lipids, proteins, DNA, and eventually leads to cell death. ROS trigger cellular apoptosis when produced at higher levels but at physiological concentration, ROS can act as a second messenger and influence gene expression, protein phosphorylation, DNA synthesis and cellular proliferation. Activated macrophages produce free radicals like reactive oxygen species (ROS) as a part of the protective immune responses. During tuberculosis, macrophage produces higher levels of ROS to kill the M. tuberculosis bacteria effectively. Hyper-production of these free radicals perturbs the redox balance leading to oxidative stress. Despite the well known activity of ROS in antibody independent cellular cytotoxicity, the effect of excess ROS in modulating the homeostasis of the immune system is not well documented. Recently, a dichotomous regulation between `T cell priming' and `effector products of macrophages' has been shown by us (Mukhopadhyay et al., 1999, J. Immunol, 163, 1786-1792), but we do not know whether ROS can act as immune effector molecule and higher levels of ROS in turn can attenuate the T cell immune functions to create an interdependent feed back inhibitory loop! These studies are funded by grants from Third World Academy of Science (TWAS), Italy and Department of Biotechnology (DBT), Govt of India. Current approaches :
Investigating alterations of macrophage effector and APC functions by NO/ROS and identification of signal transcription factors involved in such kind of modulations. This study is likely to provide new insights into the immunopharmacology of NO/ROS.
3. PPAR MEDIATED REGULATION OF GLUCOSE METABOLISM AND CORONARY HEART DISEASES : UNDERSTANDING THE MECHANISM OF ACTION : Principal Investigator: Dr. Nasreen Z. Ehtesham, National Institute of Nutrition, Hyderabad
Project Summary Coronary Heart Disease (CHD) and type-2 diabetes mellitus (T2DM) are major causes of morbidity and mortality in India. Insulin resistance, abdominal obesity, increased plasma triglycerides, decreased HDL, cholesterol, hypertension, bacterial infections coupled with low birth weight are together emerging as new risk factors within the Indian population. T2DM is characterized by target tissue resistance to insulin that cannot be overcome by cell hypersecretion. The direct link between impaired insulin action and dyslipidemias has neither been fully understood nor the underlying mechanism(s) being explored. Recently, resistin, a secretory protein expressed in adipose tissue is found to be induced during adipocyte differentiation. The levels of circulating resistin are found to be increased in diet induced or genetic form of obesity. Peroxisome proliferator-activated receptor or PPARs family of proteins play important role in obesity and diabetes mellitus. PPARs belong to a family of transcription factors which have been characterized with respect to their functional domains (ligand binding domain at the C terminal end and a DNA binding domain at the central region of the protein). Three major isoforms have been reported which have been found to be involved in the adipocyte differentiation, maintenance of energy balance and different disease within the cells. Given the importance of PPAR in glucose metabolism and coronary heart disease the PPAR interacting ligands can be identified and then screened for potential drug targets for the treatment of human insulin resistance, type 2 diabetes mellitus, hypertension and related metabolic disorders. Genetic polymorphism studies in the Indian population within the regulatory sequence and functional domains of PPAR/resistin will assist in identifying individuals at high risk for diseases related to aberrant glucose metabolism, dyslepidemia and coronary heart disease. Current approaches :
Studying Resistin/PPAR? gene polymorphism with respect to regulatory/coding sequences in clinically defined cases of obesity, type 2 diabetes mellitus and hypertension and identification of genes regulated by PPAR/resistin as well as PPAR interacting ligands.
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Last updated on : Thursday, 27th October, 2005. |
