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.
The proposed project aims to determine the role of lipid mediators in secondary injury of traumatic brain injury. Traumatic brain injury affects approximately 1.7 million individuals in the United States every year, and there are currently few treatment strategies. Inhibition of specific lipid mediators offers a safe and efficacious treatmen strategy in humans as there are medications currently available to block the same lipid mediators in other diseases.
| Okuno, Toshiaki; Gijón, Miguel A; Zarini, Simona et al. (2018) Altered eicosanoid production and phospholipid remodeling during cell culture. J Lipid Res 59:542-549 |
| Sorgi, Carlos A; Zarini, Simona; Martin, Sarah A et al. (2017) Dormant 5-lipoxygenase in inflammatory macrophages is triggered by exogenous arachidonic acid. Sci Rep 7:10981 |
| Martin, Sarah A; Brash, Alan R; Murphy, Robert C (2016) The discovery and early structural studies of arachidonic acid. J Lipid Res 57:1126-32 |
| Grevengoed, Trisha J; Martin, Sarah A; Katunga, Lalage et al. (2015) Acyl-CoA synthetase 1 deficiency alters cardiolipin species and impairs mitochondrial function. J Lipid Res 56:1572-82 |
| Martin, Sarah A; Gijón, Miguel A; Voelker, Dennis R et al. (2014) Measurement of lysophospholipid acyltransferase activities using substrate competition. J Lipid Res 55:782-91 |
