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

基本信息

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
项目类别：
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

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

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项目摘要

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 - 与父母赠款相同。对髓磷脂的损害是多发性硬化症（MS）等疾病的主要特征，并导致破坏动作潜力，轴突的损坏，最终导致退化。迄今为止，没有 MS修复或再髓的疗法，这说明了患有患者的最大需求多发性硬化症。促进remerelelination的小分子或生物制剂的功能筛选代表了主要的识别和发展MS理性疗法的障碍。最近我们实施了一本小说使用制造的微柱阵列的功能屏幕来识别大大增强的化合物少突胶质细胞透明化（Mei等，2014）。许多承诺的候选人都确定了激活或拮抗G蛋白偶联受体（GPCR）靶标。在此提案中，我们将筛选工作重点放在 GPCR小分子文库以识别/确认/验证抑制或促进髓鞘。我们认为，GPCR代表了目标的接收器和途径开发用于MS的小分子疗法。在此提案中，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，确认和验证负责调节少突胶质的新型受体和途径分化和髓鞘。 3。研究激活或阻断特定的治疗意义发育过程中和脱髓鞘后的受体。我们的初步数据确定了两个特定的GPCR，抑制（g）的一种和促进（g /g）分化和髓鞘的一种 q io 在开发期间和脱髓鞘之后。