It is vitally important to our mission that we fund unique and inspiring multiple sclerosis studies that overstep basic science, yet still fit into the goals of what we are trying to accomplish with the chance of changing the face of MS. With that we present to you our new program that furthers MS research by using smaller grants to fund unconventional studies.
Summary of Current Young Investigators Multiple Sclerosis Studies
Lilyana Amezcua, MD
Assistant Professor of Clinical Neurology Department of Neurology MS
Most current MS knowledge derives from studying MS in white individuals. While MS affects multiple backgrounds, the genetic and ethnic contributions in MS are less understood. Hispanics, a European derived population, represent an admixed population, defined as a population with recent ancestry from two or more continents- the other being Asian and in some proportions, African. These characteristics are observed in our findings where Hispanic/Latino Americans have a mixture of European and Asian traits in the way their MS behaves. Hispanic diversity in both ancestry and clinical manifestation brings advantages to studying MS.
By analyzing genes that are common to the human genome (GWAS), in particular ancestral genes that are differently distributed across populations we may be able to identify how genes influence clinical and radiological manifestation of MS and treatment response that are common to all affected by MS. This approach may be able to identify high-risk subgroups which may be at risk of progression and could benefit from earlier, aggressive treatments. This includes identification of opticospinal forms of MS more common to Asians.
Dimitrios Davalos, Ph.D.
University of California, San Francisco
Multiple sclerosis (MS) damages the myelin that surrounds and protects axons, the fibers that neuronal cells use to communicate with each other and with all muscles and organs. Without their protective myelin sheath, axons fail to conduct neuronal signals properly, and eventually, this causes the symptoms of MS. Some of the damage to myelin is done by immune cells known as microglia. These resident immune cells of the brain normally survey and protect the brain from insults. However, microglia are among the earliest cells to show signs of activation in the MS brain. Importantly, signs of early microglial activation are detectable before the onset of demyelination or the destruction of axons, an indication that they may have a key role in initiating the pathological events that lead to MS.
We recently developed cutting-edge imaging methodologies to study the sequence of events that link the activation of microglia to the formation of MS-type lesions. To do so, we use a combination of powerful microscopy and genetic technologies that allow us to follow the behavior of individual fluorescently-labeled cells inside the living brain or spinal cord, in real time. Our current studies are aimed at detailing the damaging interactions between microglia and axons and understanding the mechanisms that regulate them. Our ultimate goal is to discover targets for therapeutic intervention, by identifying the cellular events and the specific pathogenic signals that lead to loss of neuronal function in MS.
Margarita Dominguez-Villar Ph.D.
Associate Research Scientist in Neurology
Yale School of Medicine
Multiple sclerosis is a chronic inflammatory disease of the central nervous system with infiltration of activated inflammatory cells into the CNS that damage both myelin and axons. It is associated with a general loss of immune regulation as commonly seen in human autoimmune diseases. Some years ago a loss of regulatory T cell function in patients with relapsing/remitting (RR) MS was reported by the Hafler lab, although the molecular mechanisms responsible for this dysregulation are still poorly understood. Our recent data show that regulatory T cells from RRMS patients have an increased ex vivo frequency of Th1-type, IFNγ+-secreting T-bet+Foxp3+ Tregs compared to healthy controls. Our data indicate that Treg reprogramming to a newly described Th1-type of IFNγ+Foxp3+ Tregs may play an important role in the pathogenesis of MS. The goals suggested in this proposal focus on analyzing how Foxp3 binding targets are modified in Th1-Tregs due to the presence of T-bet and how these modifications are reflected in the global gene expression pattern of the cells and the defect on suppression observed in patients with MS.
The support of the Nancy Davis Foundation will help us to describe the molecular signature of Th1-Tregs as well as the ex vivo requirements for their generation. Moreover, it will help to design new therapeutic strategies for the treatment of MS.
Posted: Jun 14, 2013Los Angeles Magazine “Revel with a Cause” by Kari Mozena – July 2013