Oligl an(j demyelinating disease

最近的证据表明，脱髓鞘病变修复的限速步骤， 多发性硬化症和婴儿缺氧损伤不是新的少突胶质细胞的招募 这些祖细胞的有效成熟， 髓鞘少突胶质细胞在很大程度上，少突胶质祖细胞的成熟 由bHLH转录因子Oligl调节。研究的长期目标 这里提出的是开发Oligl成熟计划的小分子激活剂。 转录因子本身通常被认为是没有吸引力的药物靶点 因为它们与DNA和异源二聚体伴侣蛋白的相互作用涉及大的 和复杂的表面积接触。走向“下药的不可药”，我们将产生 Oligl功能的分子机制的基本见解。我们认为代孕母亲 开发Oligl激动剂的靶点很可能嵌入Oligl修饰剂中， 调节子或下游遗传靶点。基于这一观点，我们有三个具体目标： 一个是定义Oligl蛋白的翻译后修饰。目标二是检测蛋白质， 与Oligl互动目的三是确定Oligl的直接遗传靶点 我们在这里寻求的对Oligl的机械见解是所有三个项目的共同之处， 这是一个政治倡议。这些问题的答案（以及整个P01的规模经济） 将通过交互式药物机制核心（“DMC”）实现。DMC提供 集中的质谱分析、染色质免疫沉淀、单分子分析能力 DNA测序（“ChIP/Seq”和“RNA/Seq”）和生物信息学。

Recent evidence indicates that the rate-limiting step in repair of the demyelinated lesions seen in multiple sclerosis and in infants with hypoxic injury is not the recruitment of new oligodendrocyte progenitors to.the site of the damage, but rather the effective maturation of these progenitors into myelinating oligodendrocytes. To a very large extent, the maturation of oligodendrocyte progenitors is regulated by the bHLH transcription factor Oligl. The long-term objective of the research proposed here is to develop small molecule activators of the Oligl maturational program. Transcription factors per se are generally considered to be unattractive targets for drug development because their interactions with DNA and heterodimeric partner proteins involve large and complex surface area contacts. Towards "drugging the undruggable" we will generate fundamental insights into the molecular mechanisms of Oligl function. We reason that surrogate targets for development of Oligl agonists might well be embedded within the Oligl modifiers, co regulators or downstream genetic targets. With this view in mind, we have three specific aims: Aim one is to define posttranslational modifications of Oligl protein. Aim two is to detect proteins that interact with Oligl. Aim three is to identify direct genetic targets of Oligl The mechanistic insights into Oligl that we seek here are common to all three projects within this POl initiative. The answers to these questions (and economies of scale for the P01 as a whole) will be enabled by an interactive Druggable Mechanisms Core ("DMC"). The DMC provides centralized capabilities for mass spectroscopy, chromatin immunoprecipitation, single molecule ¿ DNA sequencing ("ChlP/Seq" and "RNA/Seq") and bioinformatics.