Arundhathi Venkatasubramaniam

Participant: 2014 Promise Research Symposium

Arundhathi Venkatasubramaniam
Department: Chemical, Biochemical and Environmental Engineering
Institution: University of Maryland, Baltimore County (UMBC)

ABSTRACT

Beta-amyloid fibrils and their interplay in Alzheimer’s disease through physico-chemical, signaling, and epigenetic mechanisms

Alzheimer’s disease is a neurodegenerative disorder that affects millions across the world. No effective treatment or preventive measure has yet been identified for AD because we don’t understand its intricacies. In our work, we apply analytical techniques and engineer new tools to better understand the cellular mechanism of this disease. We focus on aggregated Aβ peptide which is the chief proponent implicated in it.

We first identify how it interacts with cells and what are the possible sites of this interaction. We find that this interaction is influenced by both biological and electrochemical factors, and that certain residues play a bigger role than others. We next focus on understanding the signaling pathways that are activated by Ab peptide upon binding to the cell. Using kinetic modeling, we investigate the effect of beta-amyloid peptide on a set of signaling pathways and identify a plausible mechanism. These findings help understand how to develop therapeutics that target
beta-amyloid and inhibit its toxic activity.

A number of recent studies point to the role of DNA methylation, as a epigenetic cause or even a symptom of beta-amyloid’s toxic effect on cells. We attempted to develop a novel technique to detect methylation changes in DNA and were partly successful. We also examined global and sequence specific methylation changes in neuroblastoma as well as neural stem cells upon exposure to Aβ. The work could lead to the development of more effective stem cell therapies for use in AD and elucidate the impact of epigenetics in AD.

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BIOGRAPHICAL SKETCH

I’m a fifth year research assistant working on using engineering tools to analyze the cellular mechanisms of Alzheimer’s disease. I have also collaborated on a project to understand the mechanical properties of arteries and its correlation to cardiovascular disease. These projects were funded by grants provided from the National Science Foundation and the National Institute of Health. In the process, I enjoyed successfully mentoring other students in research and their academic development. I handled leadership roles both in research supervising undergraduate students in the laboratory as well as being a President of the Graduate association in our department coordinating a team of people in organizing social and networking events to further professional development. My future research interests are drug delivery using nanoparticles, developing novel tools to understand biological mechanisms, investigating potential therapeutics for diseases, and epigenetic mechanisms. My goal is to build on my career in order to establish myself as a sound researcher and scientist who can independently supervise new projects that contribute significantly to disease research and complete them successfully.

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GENERAL SUMMARY OF GRADUATE RESEARCH

The focus of my graduate research is in using engineering fundamentals, statistics and lab expertise in developing tools and analyzing biochemical phenomenon .Broadly, we apply a biochemical engineering approach to solving the problem of complex disease mechanisms. Specifically we used Fluorescence Energy Resonance Transfer to study the interaction of Aβ with neuron like cells. This helped identify key residues of the peptide in this interaction. We proposed a set of simple kinetic models to describe Aβ’s effect on cell signalling pathways and identified the most plausible mechanism. This helped spot early event cell interactions of the Aβ peptide in the pathogenesis of the disease and would further help screen potential inhibitors of the toxicity of the peptide.

We identified that there was a need for novel high-throughput screening methods to detect epigenetic changes as related to its application in various disease research areas. As part of our lab’s specialization in developing techniques, we designed a fluorescent magnetic bead assay that could detect methylation of a specific gene. The technique has future potential as it could be improvised into a flow chamber format that requires minute quantities of material and eliminated the need for costly hybridization techniques. In parallel, we studied global and Illumina sequence specific methylation changes upon beta-amyloid exposure , to narrow down on gene regions that
were differentially methylated , and critique what the roles of those gene promoters are and how that could solve the complexity of the mechanism of the disease.

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SELECTED LIST OF PRESENTATIONS AND PUBLICATIONS

Venkatasubramaniam, A., Drude, A., and Good, T. Role of N terminal residues in beta amyloid interaction with integrin receptor and cell surface. BBA Bio membranes (under review 1/2014).
Stephan, E. Venkatasubramaniam, A. Good, T. and Topoleski, T. The effect of oxidation on the mechanical response and microstructure of porcine arteries, Journal of Biomedical Materials Research: Part A (Epub October 2013)
Stephan, E. Venkatasubramaniam, A. Good, T. and Topoleski, T. The effect of glycation on arterial microstructure and mechanical response, JBMR: Part A (Epub July 2013)
Good T., Venkatasubramaniam A., Wilson N., , Developing New Molecular Tools to study Alzheimer’s disease, Biochemical and Molecular Engineering XVIII,(China, Research Poster) June 2013
Venkatasubramaniam A., Good T., Design of a novel high-throughput technique to detect epigenetic changes, American Chemical Society (ACS, New Orleans) (Oral Presentation) April 2013

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