Welcome to my page! I'm Sneha, a junior at Dublin High studying chemical biology in the context of cancer research. During my sophomore chemistry class, I began questioning why matter interacts the way it does, and being an aspiring physician I was drawn to study the chemistry of living things.
Glycosylation is one of the most compositionally advanced and combinatorially diverse types of post-translational modifications. In fact, I was surprised to learn that due to the macro- and micro-heterogeneity of glycan attachment on peptides, many proteomics researchers decide to exclude them from their analytes altogether! As an aspiring oncologist-glycobiologist, I see carbohydrate chemistry and proteomics as two sides of the same coin – quantifiable alterations to cells’ glycosylation patterns clearly do not occur at random, and the search for a sugar trail in the language of cell surface glycans must carry forth as we attempt to elucidate molecular drivers of disease.
Here are 3 tracks of research I'm excited about working on, and a few open questions I had while doing some readings.
Track 1: Cancer Cell Biology
Explain the sequence of mutations required to divide without apoptosis, and contrast it with the sequence of mutations required to divide without shortening the coding regions of DNA.
How were CAR T Cells engineered/personalized for Emily Whitehead, a 6 year old with acute lymphoblastic leukemia (ALL), who was completely cured?
Why do unhealthy cells develop aberrant glycoproteoforms on their cell surface?
How might we design a degrader target for the ubiquitin-proteasome pathway that is not susceptible to pharmacological resistance by cancer cells?
How can we get cells surrounding cancer cells to “snitch” on the cancer cell by detecting biomarkers that might indicate a tissue’s getting way denser than it normally would?
Track 2: Neurodegenerative Disorders
How does the downstream impact of misfolded tau proteins differ from the impact of misfolded alpha synuclein?
Can misfolded proteins cooperatively promote the aggregation of other misfolded proteins?
Is there a characteristic state of improper folding that differentiates intrinsically disordered regions from the general average?
How can the ability to conserve spatial and charge density in ion mobility spectrometry help with analyzing glycosylated intrinsically disordered proteins?
How does disordered post-translational folding impact glycosylation, and vice versa?
Track 3: Cardiovascular Pharmacology
How does beta-arrestin modulate the effects of beta-adrenergic receptor signaling in cardiac cells, particularly in the context of heart rate and blood pressure regulation?
How does biased signaling through beta-adrenergic receptors influence cardiac function differently when mediated by beta-arrestin versus G-protein signaling pathways?
Would the selective activation of beta-arrestin over G-protein pathways in beta-adrenergic receptors provide a therapeutic advantage in treating conditions like hypertension?
What are the mechanistic pathways by which beta-arrestin interacts with beta-adrenergic receptors to slow down heart rate, and how can these pathways be targeted pharmacologically?
In what ways can manipulating beta-arrestin signaling in beta-adrenergic receptors lead to novel treatments for cardiac arrhythmias and what are the potential risks?
A review of bispecific proximity based therapeutics for inhibiting cancer cell proliferationh Sneha Chidambaram* Drafting a preprint review article (2024)
Cancer cells evolve to exploit signal transduction pathways, survival adaptations, and drivers of a cell's transcriptional machinery to promote their continued survival, immune resistance and proliferation. As orthosteric and allosteric blockers of kinases emerged as efficacious inhibitors of pathways that drive oncogenicity, their inherent pharmacology ultimately leads to patients developing resistance; usually due to a point mutation that prevents the drug from controlling a target protein's occupancy. Over the past 20 years, therapeutics driven by the targeted degradation of proteins have emerged as promising alternatives to traditional inhibitors. Adopting a biomimetic strategy to induce \textit{de novo} transient associations between proteins, these degraders are composed of bivalent molecules that bind to a target protein of interest and a component of a cell's degradation machinery. In this review, we will discuss specific approaches of bispecific proximity-based therapeutics designed to inhibit cancer cell proliferation. Our goal is to highlight their mechanisms of action, analyze their interactions with endogenous cellular degradation pathways, and discuss their challenges and opportunities. We hope that understanding the principles and potential of targeted protein degradation will encourage the development of next-generation cancer therapies that have enhanced specificity, versatility, and resistance to variance caused by mutations.
Acknowledgements
My webpage uses open source code by Seyone Chithrananda, which is built on Kian Fazi's template and inspired by Jon Barron.
