Functional Screening of GPCR Small Molecule Libraries for Remyelination Therapies

用于髓鞘再生治疗的 GPCR 小分子文库的功能筛选

• 批准号: 9984143
• 负责人: Jonah R Chan
• 金额: $ 16.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9984143
• 关键词: Action Potentials; Agonist; Axon; Biological; Data; Demyelinations; Development; Disease; G-Protein-Coupled Receptors; Multiple Sclerosis; Myelin; Oligodendroglia; Pathway interactions; Patients; Regulation; Therapeutic; high throughput screening; myelination; novel; oligodendrocyte myelination; parent grant; receptor; remyelination; repaired; screening; small molecule; small molecule libraries; small molecule therapeutics

ABSTRACT – Same as parent grant. Damage to myelin is a central feature in diseases such as multiple sclerosis (MS) and results in the disruption of the action potential, damage to the axon, and ultimately leads to degeneration. To date, there are no therapies for repair or remyelination in MS and this illustrates the greatest unmet need for patients living with MS. Functional screening for small molecules or biologicals that promote remyelination represents a major hurdle to the identification and development of rational therapeutics for MS. Recently we implemented a novel functional screen using fabricated micropillar arrays to identify compounds that greatly enhance oligodendrocyte remyelination (Mei et al., 2014). Many of the promising candidates identified activated or antagonized G-protein coupled receptor (GPCR) targets. In this proposal, we focus screening efforts on GPCR small molecule libraries to identify/confirm/validate receptor targets that either inhibit or promote myelination. We believe that GPCRs represent targetable receptors and pathways for the development of small molecule therapeutics for MS. In this proposal we will: 1. Perform high-throughput screening of GPCR small molecule libraries to identify agonists and antagonists that promote myelination. 2. Identify, confirm and validate novel receptors and pathways responsible for the regulation of oligodendrocyte differentiation and myelination. 3. Investigate the therapeutic implications of activating or blocking specific receptors during development and after demyelination. Our preliminary data identifies two specific GPCRs, one that inhibits (G ) and one that promotes (G /G ) differentiation and myelination of oligodendrocytes q io both during development and after demyelination.

摘要-与父母补助金相同。 髓鞘损伤是多发性硬化症（MS）等疾病的核心特征， 动作电位的变化，轴突的损伤，最终导致退化。迄今为止，没有 治疗修复或髓鞘再生的MS，这说明了最大的未满足的需求， 女士对促进髓鞘再生的小分子或生物制剂进行功能性筛选代表了一个主要的 识别和开发MS的合理治疗方法的障碍。最近我们实施了一种新的 使用制造的微柱阵列进行功能筛选，以鉴定大大增强 少突胶质细胞髓鞘再生（Mei等，2014年）。许多有希望的候选人确定激活或 拮抗G蛋白偶联受体（GPCR）靶点。在本提案中，我们将筛选工作的重点放在 GPCR小分子文库，用于鉴定/确认/验证抑制或 促进髓鞘形成。我们认为GPCR代表了靶向受体和途径， 开发用于MS的小分子治疗剂。在该提案中，我们将：1.执行高通量 筛选GPCR小分子文库以鉴定促进髓鞘形成的激动剂和拮抗剂。2. 识别、确认和验证负责少突胶质细胞调控的新型受体和途径 分化和髓鞘形成。3.研究激活或阻断特定的 受体在发育过程中和脱髓鞘后。我们的初步数据确定了两个特定的GPCR， 一种抑制（G），一种促进（G /G）少突胶质细胞分化和髓鞘形成 q io 无论是在发育过程中还是在脱髓鞘后。