Identification of Oligodendrocyte Stimulators

少突胶质细胞刺激剂的鉴定

• 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
• 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

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）：摘要少突胶质细胞（OL）是中枢神经系统的髓鞘形成细胞，在白质形成和白质稳定性中发挥着关键作用。严重的临床疾病会影响早期发育和成年期的中枢神经系统白质。这些疾病包括脑室周围白质损伤 (PWMI)（影响高达 20% 的极低出生体重早产儿），以及糖尿病和多发性硬化症（影响儿童和成人）。目前，我们还不知道专门针对 OL 和/或 OL 前体细胞的药理学方法，可用于在发育过程中或脱髓鞘条件下刺激白质形成。由于白质损伤现在是早产儿神经系统损伤的主要原因，因此开发针对 PWMI 的新疗法将对儿童的生活产生重大有益影响。最近，我们制定了促进高通量药物筛选的策略，旨在发现刺激 OL 细胞分裂和活性的化合物。我们与耶鲁大学蛋白质组学和基因组学中心合作，建立了一个大型化合物库，针对多种细胞表面受体、离子通道和细胞内效应系统。我们已经建立了新的方法，使我们能够评估化合物对 OL 分裂和分化的影响。我们还有 PWMI 的体内模型。基于这些观察，我们假设有可能开发新的药理学方法来治疗白质疾病。为了实现这一目标，我们建议：(1) 使用高通量筛选来识别刺激 PreOL 增殖的化合物（}命中}）。 (2) 进行}命中}的剂量反应研究。 (3) 评估}命中}的毒性。 (4) 评估对 OL 基因表达的影响 本阶段 SBIR 提案中概述的实验的主要目的是鉴定刺激 OL 增殖和髓鞘形成的化合物。这项工作的长期目标是开发用于治疗早产儿、儿童和成人脑白质损伤的新型治疗剂。如果第一阶段 SBIR 提案满足我们的目标，预计第二阶段研究将在白质损伤的啮齿动物模型中进行广泛的体内测试。最终，此类研究将带来具有重大公共健康效益和商业价值的重要发现。我们还预计这些研究将导致治疗和预防白质损伤的新方法的开发。公共健康相关性 本阶段 SBIR 提案中概述的实验的主要目的是鉴定刺激 OL 增殖和髓鞘形成的化合物。这项工作的长期目标是开发用于治疗早产儿、儿童和成人脑白质损伤的新型治疗剂。