Sarah A Martin, B.Sc. Hons. - US grants

DESCRIPTION (provided by applicant): The proposed work aims to understand the role of lipid mediators in secondary disease after traumatic brain injury. The National Institute of Neurological Disorders and Stroke (NINDS) supports the on-going effort to further characterize the underlying molecular mechanisms of secondary disease, and uses that information to discover possible treatment options. We propose that leukotrienes, a class of lipid mediators, play an important role in edema and blood- brain barrier breakdown after initial trauma. The overall goal of the research training program is to expand my current knowledge of lipid mediators and their potential role in this unexplored neurodegenerative disease. During the time of this fellowship, I will be provided the opportunity to expand my knowledge of neurodegenerative diseases and current neuropharmacological treatment strategies that are in use through course work, numerous laboratory meeting, and national conferences. The long-term objective of this work is to understand and treat individuals that have experienced traumatic brain injury by blocking leukotriene production. Blocking leukotriene production temporarily has been and is successfully now being used in the treatment of asthma and shows little to no side effects, thus suggesting a safe treatment option if developed correctly. To achieve the goals outlined in the specific aims, an expert in the identification and characterization of lipid molecules, as well as an expert in neurodegeneration after traumatic brain injury will assist in the following aims: Aim 1: Determine the role that leukotrienes play i TBI through the use of a closed skull cortical impact mouse injury model. Aim 2: Use genetic knockouts and pharmacological inhibition of leukotriene biosynthesis to determine if a decreased secondary injury is observed in TBI. Aim 3: Determine the mechanistic role that infiltrating myeloid derived cells have on leukotriene biosynthesis and secondary injury in TBI.

7. Project Summary/Abstract The overall goal of this application is to elucidate the function of transmembrane 6 superfamily member 2 (TM6SF2), a protein of unknown function associated with non-alcoholic fatty liver disease (NAFLD). This goal is highly congruent with the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which supports ongoing efforts to elucidate the pathogenesis of NAFLD with a view to early detection, intervention, and prevention of chronic progressive liver disease. To identify genes that contribute to NAFLD, the Hobbs/Cohen laboratory performed an exome-wide association study for liver fat content. This screen revealed that a common variant (E167K) in TM6SF2 was associated with increased hepatic fat content and leads to progression of NAFLD to cirrhosis. The project proposed here will take advantage of the trainee?s expertise in lipid mass spectrometry to identify unique changes in lipid biochemistry in Tm6sf2 knockout mice. The Specific Aims are: Aim 1: Determine effects of TM6SF2 inactivation on hepatic and circulating lipid composition in mice. Aim 2: Establish a cell-based assay to determine the biochemical function of TM6SF2. The project will provide the basis of a multi-faceted research training program that will expand the trainee?s current knowledge of lipid biochemistry in the context of NAFLD, and provide additional training in protein-lipid biochemistry and human molecular genetics. In addition to laboratory training, the program will broaden the trainee?s knowledge of liver disease and pharmacological treatment strategies through course work, laboratory meetings and journal clubs, departmental/university lectures, and national conferences. By combining her analytical expertise in lipid mass spectrometry with biochemistry/molecular biology skills and biomedical perspective, this program will leave the trainee well-positioned to pursue a career in the biomedical sciences.