Neurodegenerative diseases, protein misfolding, inhibitor designing, chronic diseases
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.
Kajal Kamble, Aishwarya Srikant Nilakhe, Moh. Azad, Arundhati Karmakar, Sumnil Bhola
• 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
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.
- Parminder Singh, Kishore Gollapalli, Stefano Mangiola, Daniela Schranner, Mohd Aslam Yusuf, Manish Chamoli, StingL.Shi, Bruno Lopes Bastos, TriptiNair, Annett Riermeier, Elena M. Vayndorf, JudyZ.Wu, Aishwarya Nilakhe, ……., Sarika Gupta, Vidya Velagapudi, Anthony T. Papenfuss,Alaattin Kaya, Miguel GodinhoFerreir, Brian K. Kennedy, Julie K. Andersen,Gordon J. Lithgow, Abdullah Mahmood Ali, Arnab Mukhopadhyay, AarnoPalotie, Gabi Kastenmüller, Matt Kaeberlein, Henning Wackerhage, B hupinderPal, VijayK.Yadav* (2023). Taurine deficiency as a driver of aging. Science 380, eabn9257.
- Ibrar Siddique, Kajal Kamble, Sakshi Gupta, Kavita Solanki, Sumnil Bhola, Nuzhat Ahsan, Sarika Gupta * (2023). ARL6IP5 ameliorated synuclein burden by inducing autophagy viapreventing ubiquitination and degradation of ATG12. Int. J. Mol. Sci. (In press).
- Ramakrishna Voggu, Arundhati Karmakar, Venkat Swamy Puli, V. SurendraBabu Damerla, Padma Mogili, P. Amaladass, Sridhar Chidara *, Kalyan KumarPasunooti *, Sarika Gupta * (2023). Design, Synthesis, Molecular Docking Study and Biological Evaluationof Novel γ-Carboline Derivatives of Latrepirdine (Dimebon) as PotentAnticancer Agents. Molecules (in press).
- Mayuri Khandelwal, Kapil Manglani, Prabhat Upadhyay, Mohammad Azad, Sarika Gupta* (2022) AdipoRon induces AMPK activation and ameliorates Alzheimer’s like pathologies and associated cognitive impairment in APP/PS1 mice. Neurobiology of Disease 174, 105876
- Himanshu Rai, Sarika Gupta, Saroj Kumar, Jian Yang, Sushil K. Singh, Chongzhao Ran, and Gyan Modi (2022) Near-Infrared Fluorescent Probes as Imaging and Theranostic Modalities for Amyloid-Beta and Tau Aggregates in Alzheimer’s Disease. J. Med. Chem. 65, 8550−8595.
- Girija Shankar Papanai, Krishna Rani Sahoo, Betsy Reshma G, Sarika Gupta, and Bipin Kumar Gupta (2022). Role of processing parameters in CVD grown crystalline monolayer MoSe2. RSC Adv., 12, 13428.
- Girija Shankar Papanai, Samanta Pal, Prabir Pal, Brajesh S. Yadav, Preeti Garg, Sarika Gupta, S. G. Ansari, and Bipin Kumar Gupta (2021). New insight into the growth of monolayer MoS2 flakes using an indigenously developed CVD setup: a study on shape evolution and spectroscopy. Mater. Chem. Front., 5, 5429-5441.
- Pal M, Khan J, Kumar R, Surolia A, Gupta S*(2019).Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line.PLoS One. Nov 6;14(11):e0224162.
- Khan J, Salhotra S, Goswami P, Akhtar J, Jahan S, Gupta S, Sharma S, Banerjee BD, Parvez S, Gupta S*, Raisuddin S* (2019). Bisphenol A triggers axonal injury and myelin degeneration with concomitant neurobehavioral toxicity in C57BL/6J male mice. Toxicology, Dec 1;428:152299.
- Manglani K, Vijayan V, Pathak C, Khandelwal M, Singh P, Chellappa S, Yadav VK, Surolia A, Gupta S*(2019). Development and characterization of supramolecular calcitonin assembly and assessment of its interactions with the bone remodelling process. Bone, Feb 21;122:123-135.
- Khan J, Salhotra S, Ahmad S, Sharma S, Abdi SAH, Banerjee BD, Parvez S, Gupta S*, Raisuddin S*(2018). The protective effect of α-lipoic acid against bisphenol A-induced neurobehavioral toxicity. Neurochem Int. Sep;118:166-175.
- Ahsan N, Siddique IA, Gupta S*,Surolia A*(2018). A routinely used protein staining dye acts as an inhibitor of wild type and mutant alpha-synuclein aggregation and modulator of neurotoxicity.Eur J Med Chem. Jan 1;143:1174-1184.
- Viji Vijayan, Sakshi Gupta Sarika Gupta* (2017). Bone morphogenetic protein-5, a key molecule that mediates differentiation in MC3T3E1 osteoblast cell line. Biofactors, May 12. doi: 10.1002/biof.1360.
- Viji Vijayan and Sarika Gupta* (2017). Role of Osteocytes in Mediating Bone Mineralization during Hyperhomocysteinemia. Journal of Endocrinology, Jun;233(3):243-255.
- Chattopadhyay T., Ranjan R., Gupta S*, Surolia A* (2017). Bone morphogenetic protein-7 (BMP-7) augments insulin sensitivity in mice with type II diabetes mellitus by potentiating PI3K/AKT pathway. Biofactors, Mar;43(2):195-209.
- Pal M, Gupta S* (2017). Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus. Nutrition & Diabetes, Dec 12;6(12):e236.
- Ahsan N, Mishra S, Jain MK, Surolia A, Gupta S* (2015). Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibits 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* (2014). Methionine down-regulates TLR4/MyD88/NF-κBsignalling in osteoclast precursors to reduce bone loss during osteoporosis. Br J Pharmacol. 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. 2013 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 RadicBiol Med. Mar 15;61C:72-84.
- 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.
- Sarika Gupta, Manmohan Chhibber, Sharmistha Sinha, AvadheshaSurolia, (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.