Banaras Hindu University
Banaras Hindu University
Indian Institute of sciences
Neurodegenerative diseases, protein misfolding, inhibitor designing, chronic diseases
Dr. Viji Vijayan, Dr. Sakshi Gupta, Dr. Tandrika Chattopadhyay, Dr. Rajiv Ranjan Singh, Nuzhat Ahsan, Kapil Manglani, Madhuraka Pal, Ibrar Siddiqui, Shikha Salhotra, Mayuri khandelwal, Babulal Meena
Summary of Research
Research Interest in Bone Biology
The skeleton is an organ that undergoes continuous modeling and remodeling to sustain structural integrity and subserve its many roles in the body. Both bone modeling and remodeling are intricate processes influenced by diet, intrinsic hormonal milieu, metabolism, physical stimulus and genetic factors. One of the main interests of my laboratory relates to a condition called hyperhomocysteinemia (HHCY) caused by increased dietary intake of methionine, deficiency of vitamins like folic acid and vitamin B12 or genetic deficiency in enzymes like cystathionine β-synthase of methionine metabolism pathway. HHCY received increased attention in skeletal biology after its identification as a player between bone mineral density and post-menopause. In Molecular Sciences Laboratory, we use our expertise in bone cell biology to understand the etiology of skeletal conditions during HHCY.
My laboratory is interested in studying the regulatory mechanisms governing altered osteoblast and osteocyte behaviour during HHCY, with focus on identification of transcription factors that control cellular differentiation and adaptation in response to HHCY. By performing siRNA knockdown experiments in osteoblasts in vitro, we have identified FOXO1, a redox regulator to have a crucial role in the synthesis of osteoprotegerin, a decoy receptor that blocks untoward osteoclast activation. By similar molecular approach we were able to identify the role of MyD88, an adapter protein in toll like receptor-4 signaling in the expression of TRAP5b expression in developing osteoclasts. Both FOXO1 and MyD88 are proteins that have been found to be regulated by homocysteine and methionine respectively.
We are currently using a variety of approaches to define underlying molecular mechanisms by which homocysteine governs osteoblast differentiation and osteogenesis and understand the determinants involved therein employing molecular and pharmacological approaches.
Our long term goal is not only to understand molecular basis of bone loss during HHCY, but also to provide insight into the pathogenesis of a predominant clinical conditions that affect women in later years – post-menopausal osteoporosis. Post menopausal osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased susceptibility to fractures. We focus on novel interventional strategies that can open a new vista for therapeutics against post menopausal osteoporosis.
Neurodegenerative disorders: Protein misfolding, misassembly, and extracellular deposition are related to a class of diseases collectively known as “conformational diseases”, which include Alzheimer’s disease, prion disease, dialysis-related amyloidosis, familial amyloid polyneuropathy, and type II diabetes etc. Most of these diseases are incurable and fatal. The proteins and peptides related to these diseases can self-assemble into supramolecular assemblies with a common cross-ß structure. The human health impact of these diseases has motivated intensive study of the structure and growth of amyloid fibrils. A mechanistic understanding of the amyloid-assembly process will provide new holds and probes for the physiological interactions that cause amyloidosis. This will allow better approaches to the prevention of amyloid formation and new diagnostics for early detection of amyloid-related diseases. Our lab is involve in identifying the important modifications in the protein sequence that leads to change in its folding and interactions with other protein and ultimately leads to its misfolding and aggregation in to amyloid fibril. These studies may help understanding the intracellular events that leads to cell death on extracellular deposition of protein fibril or intermediates of fibril formation which in turn helps in designing specific therapeutic agents targeting different steps of disease progression for the effective treatment of the disease.We also hypothesis that blocking and/or reversing amyloid formation will be an effective treatment for diseases involving organ failure due to amyloidosis. This requires detailed knowledge of the mechanisms of amyloid growth and the factors that influence the (dis)aggregation rates at all stages of amyloid assembly. We have chosen three diseases: Parkinson's disease (PD), Alzheimer’s disease (AD), and transthyretin-related amyloidosis to address these issues. We also work on to understand the mechanisms and factors that modulate the activity, structure and expression of glutamate transporters and endoplasmic reticulum associated proteins in neurological diseases.
Awards / Fellowships
Indian Academy of Biomedical Sciences- Smt. Kusum Sharma Award- 2014
SERB women excellence award 2013 -Department of Science and Technology, New Delhi, India.
NASI- platinum jubilee young scientist awards (2011)
Visiting Scientist to University of Miami, Miami, U.S.A.- 1st -31st July 2010.
- Ahsan N, Mishra S, Jain MK, Surolia A, Gupta S* (2015). Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of Wild type and Mutant α-Synuclein. Sci Rep. May 18;5:9862
- Pasi S, Kant R, Gupta S, Surolia A (2015). Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis. Biomaterials. Feb;42:121-33.
- Pathak C, Ranjan Singh R, Yadav S, Kapoor N, Raina V, Gupta S*, Surolia A* (2014). Design, synthesis and biological evaluation of benzothiophene carboxamide derivatives as analgesics and anti-inflammatory agents. IUBMB Life, Mar 26.
- Vijayan V, Khandelwal M, Manglani K, Gupta S*, Surolia A* (2013). Methionine down-regulates TLR4/MyD88/NF-κB signalling in osteoclast precursors to reduce bone loss during osteoporosis. Br J Pharmacol. 2014 Jan;171(1):107-21.
- Raina V, Gupta S*, Yadav S, Surolia A* (2013). Simvastatin induced neurite outgrowth unveils role of cell surface cholesterol and acetyl CoA carboxylase in SH-SY5Y cells. PLoS One. Sep 11;8(9):e74547.
- Vijayan V, Khandelwal M, Manglani K, Singh RR, Gupta S*, Surolia A* (2013). Homocysteine alters the osteoprotegerin/RANKL system in the osteoblast to promote bone loss: pivotal role of the redox regulator forkhead O1. Free Radic Biol Med. 2013 Mar 15;61C:72-84.
- Tomar D, Khan T, Singh RR, Mishra S, Gupta S, Surolia A, Salunke D M (2012). Crystallographic study of novel transthyretin ligands exhibiting negative-cooperativity between two T4 binding sites. Plos One, 2012;7(9):e43522.
- Banerjee T, Singh RR, Gupta S, Surolia A, Surolia N (2012). 15-Deoxyspergualin hinders physical interaction between basic residues of transit peptide in PfENR and Hsp70-1. IUBMB Life. Jan;64(1):99-107
- Tripathi R, Samadder T, Gupta S, Surolia A, Shaha C (2011). Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. Mol Cancer Ther. Feb; 10(2):255-68.an;64(1):99-107
- Gupta S, Chattopadhyay T, Pal Singh M, Surolia A (2010). Supramolecular insulin assembly II for a sustained treatment of type 1 diabetes mellitus. Proc Natl Acad Sci U S A. Jul 27;107(30):13246-51.
- Gupta S*, Babu P, Surolia A*(2010). Biphenyl ethers conjugated CdSe/ZnS core/shell quantum dots and inter pretation of the mechanism of amyloid fibril disruption. Biomaterials. Sep;31(26):6809-22.
- Chopra T, Banerjee S, Gupta S, Yadav G, Anand S, Surolia A, Roy RP, Mohanty D, Gokhale RS (2008). Novel Intermolecular Iterative Mechanism for Biosynthesis of Mycoketide Catalyzed by a Bimodular Polyketide Synthase. PLoS Biology. 6(7):e163
- Sarika Gupta, Manmohan Chhibber, Sharmistha Sinha, Avadhesha Surolia, (2007). Design of Mechanism Based Inhibitors of Transthyretin Amyloidosis: Studies with Biphenyl Ethers and Novel Structural Templates. Journal of Medicinal Chemistry. 50(23):5589-99.
- Sarika Gupta, Rahul Modak, Namita Surolia, Avadhesha Surolia (2009). Partial molar volumes of acyl carrier proteins are related to their states of acylation. Biochemical and Biophysical Research Communications, 380, 4, 20, 763-768
- Rathaur S, Yadav M, Gupta S, Anandharaman V, Reddy MV (2008). Filarial glutathione-S-transferase: A potential vaccine candidate against lymphatic filariasis. Vaccine. 26(32):4094-100.
- Gupta S, Singh A, Yadav M, Singh K, Rathaur S (2007). MALDI mass sequencing and characterization of filarial glutathione-S-transferase. Biochemical and Biophysical Research Communication. 4; 356(2):381-385.
- Sarika gupta, Y. P. Bhandari, M.V.R. Reddy, B. C. Harinath, S. Rathaur (2005). Setaria cervi Glutathione-S-transferase: Immunoprophylactic potential against filarial parasite Brugia malayi. Experimental Parasitology, 109 (4), 252-255.