BLR&D Research Career Scientist Award Application

Jesse Brown Va Medical Center, Chicago IL

Investigators

Linked publications & trials

Abstract

The major area of our research is to understand the causes of, and development treatments for neurodegenerative diseases and conditions, in particular Multiple Sclerosis (MS). This work includes repurposing drugs that are FDA-approved for other indications but show benefit in animal models of MS, making it easier to bring them to the clinic. A better understanding of how these diseases start and evolve, and identification of interventions will help reduce disease symptoms, as well as social and economic burdens. Our MS studies have been supported by Merit grants, and recently have developed into studies of drugs which increase or accelerate remyelination. For this we make use of both animal models as well as cell culture studies, focusing attention on oligodendrocytes, the cells that produce myelin; and astrocytes, cells which provide trophic support and energy substrates to neurons and oligodendrocytes. Recently we discovered that induction of metabolic dysfunction in astrocytes, in this case by reducing expression of an enzyme that is a risk factor for MS, causes the cells to reduce production of Coenzyme A, a protein involved in numerous processes including the citric acid cycle, fatty acid synthesis, and regulation of iron accumulation. These deficiencies can lead to cell damage and death of astrocytes, as well as of neighboring cells due to reduced astrocyte generation of protective factors. Our studies have led us to investigate genetic risk factors that predispose one to developing MS, and determining the prevalence of these factors in different populations including Veterans of different ethnic backgrounds. Our original studies showed that a nucleotide variant in a gene called STK11 is present at higher levels in women with MS; and we confirmed it is also increased in African-Americans as well as White MS patients; and differs depending upon the type of MS disease. From this work we began studies of the microbiome of MS patients, looking at bacterial species present in saliva, an easy to access resource. We first showed that the oral biome differs in MS patients with different disease; and currently are determining how it differs between MS patients and healthy controls. A third project in the lab, funded by an NIH U01 grant is to develop methods to reduce the levels of highly toxic rodenticides in the body. This is an emerging worldwide crisis, as demonstrated by the outbreaks of poisoning that have occurred in Midwest US; Tampa, FL; and Haifa, Israel. We have identified one treatment which reduces the biological half lives of rodenticides by up to 5-fold, and are now optimizing treatments to fully eliminate them from the body. This work also extends to determining how these rodenticides damage other tissues, including in the CNS, and if myelin levels are reduced. We have also begun to analyze the gut microbiome of animals exposed to rodenticides, and find significant differences that could influence rodenticide metabolism and elimination.