The curious case of PARP1 in CNS myelin formation and repair

PARP 1在中枢神经系统髓鞘形成和修复中的奇怪案例 目前的抗炎药物减少免疫攻击，但在预防神经系统疾病方面无效。 多发性硬化（MS）的进展，最常见的中枢神经系统脱髓鞘疾病 (CNS)在美国有40万人感染了这种无法治愈的疾病。再髓鞘化失败，主要是由于 少突胶质细胞从少突胶质细胞祖细胞分化受损（即OPC受损 分化）是MS神经系统进展的主要原因之一。促髓鞘再生疗法 代表了与当前免疫抑制药物组合用于治疗MS的有希望的选择。 然而，很少有药物可用于靶向髓鞘修复。我们的长期目标是发现 用于治疗脱髓鞘疾病的促进髓鞘再生的策略。这项建议的目的是 解决聚（ADP-核糖）聚合酶1（PARP 1）是否以及如何调节OPC分化和髓鞘形成 并确定PARP 1介导的通路在髓鞘修复中的治疗价值。PARP 1是一个多方面的 在癌症生物学中被广泛研究的核蛋白。一旦激活，PARP 1催化 将聚（ADP-核糖）单元共价添加到其靶蛋白上，这一过程称为PAR化， 被聚（ADP-核糖）糖水解酶（PARG）逆转。这背后的临床原理 提示活动性而非慢性MS病变中的少突胶质细胞谱系细胞显示升高的PARP 1 活性，表明PARP 1可能是促进髓鞘再生治疗的潜在靶点。但我们的 目前对PARP 1在少突胶质细胞生物学和病理学中的了解非常有限， 在髓鞘再生中的价值还有待确定。核心假设是PARP 1通过其 酶活性，是OPC分化和髓鞘形成的内在双模型驱动因素， 用来促进髓磷脂修复我们的中心假设是建立在概念和方法论上的 我们在体外和体内的遗传和药理学操作的初步数据奠定的基础。的 将在三个特定目的中检验假设：1）确定PARP 1缺失对OPC分化的影响 2）确定PARP 1调节OPC分化和髓鞘形成的机制; 和3）确定PARP 1介导的PAR化的功能丧失和获得对髓鞘修复的影响。我们 将通过使用我们实验室产生的独特的转基因模型来实现这三个目标。的 一项拟议中的研究意义重大，因为它将探讨PARP 1在髓鞘修复中的治疗潜力 并为制定促进髓鞘再生的策略奠定概念基础。预期成果将 具有重要的积极影响，因为它们将建立关于功能的第一个概念图 PARP 1在中枢神经系统髓鞘形成和修复中的作用机制，为进一步研究PARP 1在中枢神经系统髓鞘形成和修复中的作用机制提供了新的资料。 干预PARP 1介导的PARylation作为促进髓鞘再生治疗的有前途的选择。

The curious case of PARP1 in CNS myelin formation and repair Current anti-inflammatory drugs diminish immune attacks yet are ineffective in preventing neurological progression of multiple sclerosis (MS), the most common demyelinating disorder of the central nervous system (CNS) with no cure affecting ~ 400,000 people in the USA. Remyelination failure, primarily resulted from impaired differentiation of oligodendrocytes from oligodendrocyte progenitor cells (i.e. impaired OPC differentiation), is one of the major causes for MS neurological progression. Remyelination-promoting therapy represents a promising option in combination with current immunosuppressive medications, for treating MS. However, few medications are available for targeting myelin repair. Our long-term goal is to discover remyelination-promoting strategies for treating demyelinating disorders. The objective of this proposal is to address if and how poly(ADP-ribose) polymerase 1 (PARP1) regulates OPC differentiation and myelination and determine therapeutic values of PARP1-mediated pathways in myelin repair. PARP1 is a multi-faceted nuclear protein that has been extensively scrutinized in cancer biology. Upon activation, PARP1 catalyzes the covalent addition of poly(ADP-ribose) units to its target proteins, a process called PARylation which can be reversed by the enzyme poly(ADP-ribose) glycohydrolase (PARG). The clinical rationale underlying this proposal is that oligodendroglial lineage cells in the active but not chronic MS lesions display elevated PARP1 activity, suggesting that PARP1 may be a potential target for remyelination-promoting therapy. However, our current knowledge of PARP1 in oligodendroglial biology and pathology is extremely limited and its therapeutic value in remyelination has yet to be determined. The central hypothesis is that PARP1, acting through its enzymatic activity, is an intrinsic dual-model driver of OPC differentiation and myelination which could be harnessed to promote myelin repair. Our central hypothesis is built on the conceptual and methodological foundations laid by our preliminary data of genetic and pharmacological manipulations in vitro and in vivo. The hypothesis will be test in three specific aims: 1) determine the effect of PARP1 depletion on OPC differentiation and myelination; 2) define the mechanisms underlying PARP1-regulated OPC differentiation and myelination; and 3) determine the effects of loss- and gain-of-function of PARP1-mediated PARylation on myelin repair. We will pursue these three aims by employing unique transgenic models generated in our laboratory. The proposed research is significant because it will interrogate the therapeutic potential of PARP1 in myelin repair and lay the conceptual groundwork to develop remyelination-promoting strategies. The expected outcomes will have an important positive impact because they will establish the first conceptual picture regarding the function and mechanism of PARP1 in CNS myelin formation and repair and they will provide new data justifying intervening PARP1-mediated PARylation as a promising option for remyelination-promoting therapy.