Collaborative MS Research Center Award
$742,500; 11/1/09-10/31/14
Principal Investigator
David Hafler, MD
Yale University
New Haven, CT
Purpose
Apply novel technologies to understand how newly identified MS risk genes alter biological mechanisms that lead to susceptibility to the disease.
Co-investigators
Vijay K. Kuchroo, DVM, PhD
Harvard Medical School
Richard A. Young, PhD
Whitehead Institute, MIT
Summary
This Collaborative Center brings together two of the major laboratories of MS research (Dr. Hafler at Yale and Dr. Kuchroo at Harvard), with expertise in MS immunology and genetics, with the Whitehead Institute at MIT (Dr. Young), who has expertise in determining factors that regulate how genes are controlled. The goal is to translate the newly discovered MS risk genes into biological, and ultimately therapeutic, understanding. Establishing the direct link between the MS risk genes and the biological mechanisms they are involved in is critical for identifying novel therapeutic interventions.
First Dr. Young, who has never before applied his expertise to questions surrounding MS, will direct the creation of high-resolution “maps” of key genes in human immune cells, including immune cells that are active in either ramping up the immune attack or inhibiting it during the course of MS. He will do this by applying a new large-scale technology developed in his own lab, called “Whole-Genome Chromatin IP Sequencing,” in which proteins of interest bind to specific DNA sequences in immune cells and then those sequences are analyzed.
Next, Dr. Hafler will compare these maps to data that is being generated by large-scale genome scans of people with MS. New technologies will allow for fine sequencing of genome regions of particular interest. This process will allow the discovery of those regulatory regions that may be disrupted by previously identified MS risk gene variants. The team believes this information will lead them directly to the associated biological pathway that may be altered by the genes.
Dr. Kuchroo will add his considerable expertise in the development of rodent models that will help tease out functions and consequences of these gene alterations. The identified pathways will then be extensively studied in models by generating genetically engineered mice and/or by replacing mouse genes with human genes harboring MS risk variants.
Taken together, the team will build a platform through which they will explore the regulation of MS risk genes and how they influence immune system behavior. By combining expertise across disciplines, this Collaborative Center should make major steps toward unraveling the biological pathways that are affected by MS risk genes, and in the process uncover novel therapeutic avenues.