सारिका गुप्ता

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:
• 2014: Smt. Kusum Sharma Oration Award, Indian Academy of Biomedical Sciences
• 2013: SERB-DST women excellence award
• 2011: NASI Young scientist award
• 2010: Visiting scientist to University of Miami

Patents:
1. Composition useful for the treatment of inflammatory disease or disorders, 401243, India.
2. Peptide complex with immunomodulatory and anti-inflammatory function, 11,447,534, USA.
3. Peptide complex with immunomodulatory and anti-inflammatory function, 393755, India.
4. Composition useful for treatment of diabetes & disorder, 298991, India.
5. A method for treating metabolic disorders including type-1 and type-2 diabetes mellitus. 8940691, USA.
6. Process for preparing supramolecular calcitonin assemblies (SCA).EP2282763, Europe.

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