Identification of Oligodendrocyte Stimulators

DESCRIPTION (provided by applicant): Abstract Oligodendrocytes (OLs) are the myelinating cells of the central nervous system and play a critical role in white matter formation and white matter stability. Serious clinical disorders affect central nervous sy stem white matter during early development and in adulthood. These conditions include periventricular white matter injury (PWMI), which affects up to 20% of very low birthweight premature infants, and diabetes mellitus and multiple sclerosis, which affect both children and adults. Presently, we are unaware of pharmacological approaches that specifically target OLs and/or OL precursor cells that can be applied to stimulate white matter formation either during development or in demyelination conditions. Becau se white matter injury is now the leading cause of nervous system injury in premature infants, developing new treatments for PWMI will have a major beneficial impact on the lives of children. Recently, we have developed strategies to facilitate high-throug hput drug screening aimed at discovering compounds that stimulate OL cell division and activity. In collaboration with the Yale Center for Proteomics and Genomics, we have established a large compound library that targets a wide array of cell surface recep tors, ion channels, and intracellular effect systems. We have established new approaches that allow us to assess effects of compounds on OL division and differentiation. We also have in vivo models of PWMI. Based on these observations, we hypothesize that it is possible to develop new pharmacological approaches to treat white matter disorders. To achieve this goal we propose to: (1) Use high-throughput screening to identify compounds ( hits ) that stimulate PreOL proliferation. (2) Perform dose-response stu dies of hits . (3) Assess toxicity of hits . (4) Assess influences on OL gene expression The primary objective of the experiments outlined in this Phase I SBIR proposal is to identify compounds that stimulate OL proliferation and myelination. The long-te rm goal of this work is to develop novel therapeutic agent for the treatment of white matter injuries in premature infants, children and adults. If this Phase I SBIR proposal meets our goals, Phase II studies are envisioned in which extensive in vivo testi ng will be performed in rodent models of white matter injury. Ultimately, research such as this will lead to important discoveries with significant public health benefit and commercial value. We also anticipate that these studies will lead to the developme nt of novel approaches for treating and preventing white matter injury. PUBIC HEALTH RELEVANCE The primary objective of the experiments outlined in this Phase I SBIR proposal is to identify compounds that stimulate OL proliferation and myelination. The lon g-term goal of this work is to develop novel therapeutic agent for the treatment of white matter injuries in premature infants, children and adults.