The curious case of PARP1 in CNS myelin formation and repair

PARP1 在中枢神经系统髓磷脂形成和修复中的奇特案例

• 批准号: 10445766
• 负责人: Fuzheng Guo
• 金额: $ 50.01万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445766
• 关键词: Ablation; Address; Affect; Animal Model; Anti-Inflammatory Agents; Antibodies; Area; Biology; Brain; Cancer Biology; Cell Death; Cell Differentiation process; Cell Lineage; Cell Nucleus; Cells; Clinical; DNA Repair; Data; Demyelinating Diseases; Demyelinations; Detection; Enzymes; Failure; Family; Family member; Foundations; Gene Expression; Genetic; Genome Stability; Glycoside Hydrolases; Goals; Histones; Immune; Immunosuppressive Agents; Impairment; In Vitro; Inflammation; Knowledge; Laboratories; Lead; Lesion; Mediating; Methodology; Mission; Modality; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Neuraxis; Neurologic; Nuclear Protein; Oligodendroglia; Outcome; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacology; Phenocopy; Play; Poly(ADP-ribose) Polymerases; Polymerase; Process; Proteins; Public Health; Research; Role; Sagittaria; Signal Transduction; Spinal Cord; Testing; Therapeutic; Transgenic Model; United States National Institutes of Health; cancer cell; central nervous system demyelinating disorder; gain of function; genetic approach; genetic manipulation; in vivo; inhibitor; insight; member; myelination; novel; oligodendrocyte progenitor; poly ADPR glycohydrolase inhib; pre-clinical; prevent; remyelination; repaired; stem cells

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.

PARP1在中枢神经系统髓鞘形成和修复中的奇特病例 目前的抗炎药物可以减少免疫攻击，但对预防神经系统疾病无效 多发性硬化(MS)的进展，这是最常见的中枢神经系统脱髓鞘疾病 (CNS)在美国有大约40万人受到无法治愈的影响。重新髓鞘形成失败，主要原因是 少突胶质细胞从少突胶质前体细胞分化为少突胶质细胞受损(即OPC受损) 分化)，是MS神经进展的主要原因之一。促髓鞘再生疗法 与目前的免疫抑制药物相结合，是治疗多发性硬化症的一个有希望的选择。 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 治疗脱髓鞘疾病的促进重新髓鞘形成的策略。这项建议的目的是 阐述聚(ADP-核糖)聚合酶1(PARP1)是否以及如何调节OPC分化和髓鞘形成 并确定PARP1介导的髓鞘修复通路的治疗价值。PARP1是一个多方面的 在癌症生物学中被广泛研究的核蛋白。在激活时，PARP1催化 将聚(ADP-核糖)单元共价加成到其目标蛋白质上，这一过程称为PAR化，可以 被聚腺苷二磷酸核糖水解酶(PARG)逆转。这背后的临床理论基础 建议在活动期但非慢性MS病变中的少突胶质细胞系细胞显示PARP1升高 活性，提示PARP1可能是促进再髓鞘形成治疗的潜在靶点。然而，我们的 目前对PARP1在少突胶质细胞生物学和病理学方面的了解极其有限，其治疗 髓鞘再生的价值还有待确定。中心假设是PARP1，通过其 酶活性，是OPC分化和髓鞘形成的内在双重模式驱动因素，这可能是 被用来促进髓鞘修复。我们的中心假设建立在概念和方法论的基础上 我们在体外和体内的遗传和药理操作的初步数据奠定了基础。这个 假设将在三个特定的目的进行检验：1)确定PARP1缺失对OPC分化的影响 2)明确PARP1调控OPC分化和髓鞘形成的机制； 3)确定PARP1介导的PAR化对髓鞘修复的功能丧失和功能获得的影响。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。这个 拟议的研究具有重要意义，因为它将询问PARP1在髓鞘修复中的治疗潜力 并为开发促进再髓鞘形成的策略奠定了概念性基础。预期的结果将是 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性画面 和PARP1在中枢神经系统髓鞘形成和修复中的作用机制，将提供新的数据支持 干预PARP1介导的PAR化是促进髓鞘再生治疗的一种有前景的选择。