1. Understanding the mechanisms underlying lifespan extension by natural products.

Aging is a complex process characterized by a progressive decline in physiological function, followed by dysfunction, and ultimately, death. Aging can be affected by various factors, such as disease, injury, nutrition, exercise, stress, and environmental factors. The aging is the major cause for the rapid rise in age-related diseases, posing a burden on our societies if we fail to develop strategies to prevent the onset of age-associated diseases. Effectively slowing aging, will improve human function with age, prevent disease and, in short, extend human healthspan, a greatly desirable goal that will simultaneously increase life quality and offset spiraling healthcare costs. Therefore, one of the major goals of our lab is to identify and characterize novel anti-aging molecules from natural sources such as from dietary and medicinal plants. Various scientific efforts slow the process of aging and extend the lifespan or healthspan have led to the identification of a few small molecules such as rapamycin and metformin. However, potential side effects of modern medicines are a concern, as well as the difficulty of getting regulatory approval for drugs to slow aging. Therefore, natural products like herbal medicines and/or phytomedicines that have anti-aging activity could be of great value because of they are safe for human use. Here, we use the budding yeast Saccharomyces cerevisiae as the model organism for small molecule identification. Moreover, the vast knowledge of cellular processes in yeast makes it a premier organism for identifying mechanisms by which small molecules exert their effects. We are also comparatively studying the mechanism of action of known lifespan extending molecules including, rapamycin, metformin, ibuprofen, spermidine, resveratrol etc.

2. Understanding the physiological significance of histone H3 clipping in budding yeast

The structural and functional unit of chromatin is called nucleosomes. The nucleosomes are composed of highly basic histone proteins namely, H2A, H2B, H3 and H4 that organizes into compact histone octamer wrapped by 147 bp of DNA. The tail region of all histones remains outside of the nucleosome globular core structure and are post-transnationally modified (PTM) by chromatin modifying enzymes. There are various kinds of reversible histone PTMs known, such as acetylation, methylation, phosphorylation, sumoylation, ubiquitylation, ADP-ribosylation, etc. These PTMs regulate chromatin structure by varying the interaction between histones and DNA, besides the recruitment of different epigenetic modifiers that modulates the chromatin associated process. Apart from these reversible histone PTMs, the permanent irreversible histone modifications are also reported. Histone clipping is one such modification in which the proteolytic clipping of histone tail occurs. The histone H3 clipping events have been experimentally demonstrated in many cellular systems including budding yeast; however, the identity of the protease and its physiological significance has just begun or not explored yet. Our goal is to identify and characterize the H3 clipping protease and to understand the physiological significance of H3 clipping using the budding yeast Saccharomyces cerevisiae as the model organism.

3. Understanding the evolution and implications of emerging SARS-CoV-2 variants.

The world has experienced a health emergency due to the Coronavirus disease (COVID-19), caused by an enveloped positive-sense single stranded virus, the severe acute respiratory syndrome coronavirus (SARS-CoV-2). The SARS-CoV-2 spread worldwide within a few months and its rapid global reach provided the virus an ample opportunity to mutate and for natural selection to act. The investigation on the genomic variation acquired by SARS-CoV-2 is indispensable for understanding the epidemiology, pathogenesis; devise preventive measures and treatment strategies against COVID-19. Most likely, due to these mutations in the SARS-CoV-2 genome the new and more resistant strains are constantly getting generated, which can successfully evade host immune system and nullify pharmacological molecules designed against them. More importantly, if the mutated viruses have better fitness than its counterparts they get selected by natural selection and led to appearance of new variants. Therefore, genomic surveillance of SARS-CoV-2 is needed to understand the evolution and future course of pandemic. Towards this, bioinformatical approaches play key role by predicting the impact of mutations on viral protein structure and function. Here, our goal is to use computational tools to investigate the variations occurring in the SARS-CoV-2 genome from different geographical regions of India and other countries and to understand its implication on structure and function of SARS-CoV-2 proteins.

4. Understanding the effect of natural products, drugs and environmental contaminants on cellular homeostasis.

We are identifying and characterizing the intracellular targets of various small molecules that humans are frequently exposed, to understand their beneficial and hazardous effect.