Identification of Oligodendrocyte Stimulators

少突胶质细胞刺激剂的鉴定

基本信息

批准号：
7479987
负责人：
SEIYU HOSONO
金额：
$ 15.09万
依托单位：
JS GENETICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7479987
关键词：
Adult Affect Cell Surface Receptors Cell division Cells Child Clinical Collaborations Condition Demyelinations Development Diabetes Mellitus Disease Dose Gene Expression Genetic Genomics Goals Health Benefit Human In Vitro Ion Channel Lead Libraries Life Low Birth Weight Infant Modification Multiple Sclerosis Nervous System Trauma Neuraxis Oligodendroglia Periventricular white matter injury Pharmaceutical Preparations Phase Phase II Clinical Trials Play Preclinical Drug Evaluation Premature Infant Proteomics Public Health Research Rodent Model Role Scientist Small Business Funding Mechanisms Small Business Innovation Research Grant System Testing Therapeutic Agents Toxic effect United States National Institutes of Health Universities Very Low Birth Weight Infant White Matter Disease Work abstracting base experience high throughput screening in vivo in vivo Model myelination novel novel strategies novel therapeutics oligodendrocyte precursor precursor cell prevent programs research study response white matter white matter injury

项目摘要

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 system 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. Because 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-throughput 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 receptors, 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 studies 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-term 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 testing 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 development 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 long-term goal of this work is to develop novel therapeutic agent for the treatment of white matter injuries in premature infants, children and adults.

描述（由申请人提供）：抽象的少突胶质细胞（OLS）是中枢神经系统的骨髓细胞，在白质形成和白质稳定性中起关键作用。严重的临床疾病会影响中枢神经系统在早期发育和成年期间。这些疾病包括脑室周围的白质损伤（PWMI），该疾病会影响高达非常低的出生体重早产儿的20％，以及糖尿病和多发性硬化症，这会影响儿童和成人。目前，我们不知道专门针对OLS和/或OL前体细胞的药理方法，这些方法可用于刺激在发育过程中或在脱髓鞘条件下刺激白质形成。由于白质损伤现在是过早婴儿神经系统损伤的主要原因，因此为PWMI开发新的治疗方法将对儿童的生活产生重大的有益影响。最近，我们开发了促进高通量药物筛查的策略，旨在发现刺激OL细胞分裂和活性的化合物。与耶鲁大学蛋白质组学和基因组学中心合作，我们建立了一个针对各种细胞表面受体，离子通道和细胞内效应系统的大型化合物库。我们已经建立了新方法，使我们能够评估化合物对OL分裂和分化的影响。我们还具有PWMI的体内模型。基于这些观察结果，我们假设可以开发新的药理方法来治疗白质疾病。为了实现此目标，我们建议：（1）使用高通量筛选来识别刺激Preol增殖的化合物（} hitts}）。（2）进行phits的剂量反应研究}。（3）评估} hits的毒性}。（4）评估对OL基因表达的影响，该阶段I SBIR提案中概述的实验的主要目标是鉴定刺激OL增殖和髓鞘形成的化合物。这项工作的长期目标是开发新型的治疗剂来治疗早产儿，儿童和成人的白质损伤。如果此阶段I阶段SBIR提案达到了我们的目标，则设想了II期研究，其中将在白质损伤的啮齿动物模型中进行大量体内测试。最终，诸如此类的研究将导致具有巨大公共卫生利益和商业价值的重要发现。我们还预计，这些研究将导致开发用于治疗和预防白质损伤的新方法。耻骨健康相关性，在此I阶段I SBIR提案中概述的实验的主要目标是鉴定刺激OL增殖和髓鞘形成的化合物。这项工作的长期目标是开发新型的治疗剂来治疗早产儿，儿童和成人的白质损伤。