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New trans-institutional program to focus on genetic variations, disease

May. 9, 2019, 9:03 AM

From left, Brinda Selvaraj, PhD, Jonathan Sheehan, PhD, Hassane Mchaourab, PhD, and colleagues are part of the new trans-institutional Program in the Molecular Basis of Genetic Diseases. (photo by Steve Green)

by Bill Snyder

Vanderbilt has established a program to help researchers determine more precisely how genetic variations contribute to disease and what potentially can be done to put them right.

The trans-institutional Program in the Molecular Basis of Genetic Diseases was established this spring to encourage experts across campus in diverse fields, from protein structure and function to animal models of disease, to work together to answer particularly difficult biological questions.

Growing numbers of health conditions are being linked to variations in the genetic code. The problem is, which variations lead to disease? Which genes are “expressed” or translated into proteins? And once expressed, how do these aberrant proteins disrupt normal physiology?

“Even though you have the DNA sequence, these are questions you’re left wondering about,” said the program’s founder and director, Hassane Mchaourab, PhD, Louise B. McGavock Professor in the School of Medicine’s Department of Molecular Physiology and Biophysics, and professor of Chemistry in the College of Arts and Science.

To help clinicians answer these questions, the program applies cutting-edge techniques in structural biology, biochemistry and biophysics to bridge the mechanistic gap between genotypes (genes or sets of genes) and phenotypes (physical characteristics that reflect the interaction of genetic and environment).

Specifically, it adds experimental verification to computational prediction — the critical step for turning a hypothesis into knowledge. The aim is to directly impact patient care. Using these techniques, for example, program investigators can investigate disease-linked mutations of proteins and then use this knowledge for new therapies and improved treatment.

According to its new website, https://my.vanderbilt.edu/mbgd, “the vision of this program is to catalyze connections, collaborations and cross-talk between clinicians, geneticists and basic scientists, thereby creating teams focused on understanding the relationships between genes and phenotypes.”

Visitors to the website are invited to complete a survey listing the disease-linked genes and proteins they are investigating. So far 40 responses have been received. The information will be used to identify opportunities for collaboration.

Brinda Selvaraj, PhD, research instructor in Molecular Physiology and Biophysics, is program manager.

As an example of the program’s collaborative spirit, Selvaraj is working with Erkan Karakas, PhD, assistant professor of Molecular Physiology and Biophysics, to determine how mutations in NMDA receptors, key players in learning and memory in the brain, are associated with neurodevelopmental disorders including mental retardation and epileptic aphasia.

The researchers hope to advance understanding of “the subtle and complicated role of the receptors, leading to new insights into precision therapy for neuronal disorders. Hyper- and hypo-activation of NMDA receptors have been implicated in neurological disorders, including stroke, schizophrenia, epilepsy, Alzheimer’s disease and anti-NMDA receptor encephalitis.

Mchaourab, recipient of Vanderbilt University’s Stanley Cohen Award for Outstanding Contributions to Research in 2018, is widely regarded as a world leader in mechanistic structural biology, particularly in methods for determining how proteins bend, twist or otherwise catalyze a given reaction.

Characterizing the “dynamic dimension” of protein structures is essential to understanding multi-drug resistance in infectious disease and cancer, for example, as well as brain disorders linked to the dysregulation of neurotransmitter levels and protein aggregation.

Funded by the office of the Dean of Basic Sciences, the new program builds upon and expands the Program in Personalized Structural Biology led by Jens Meiler, PhD, Tony Capra, PhD, and Jonathan Sheehan, PhD.

Meiler is Stevenson Professor of Chemistry and professor of Pharmacology and Biomedical informatics. Capra is assistant professor of Biological Sciences, Biomedical Informatics and Computer Science. And Sheehan is research associate professor of Biochemistry.

The Program in the Molecular Basis of Genetic Diseases also was developed in partnership with Todd Edwards, PhD, associate professor of Medicine and an expert on genetic determinants of complex diseases.

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