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: 10621372
• 负责人: Fuzheng Guo
• 金额: $ 50.63万
• 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/10621372
• 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; Central Nervous System; Clinical; Curiosities; 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; Lesion; Mediating; Methodology; Mission; Modality; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Neurologic; Nuclear Protein; Oligodendroglia; Outcome; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Phenocopy; Play; Poly Adenosine Diphosphate Ribose; 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; loss of function; member; myelination; novel; oligodendrocyte progenitor; pharmacologic; 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.

CNS髓磷脂形成和修复中PARP1的奇怪情况 当前的抗炎药减少了免疫攻击，但在预防神经系统方面却无效 多发性硬化症（MS）的进展，这是中枢神经系统最常见的脱髓鞘障碍 （CNS）没有治愈能力影响约40万人。重新性失败，主要是由 少突胶质细胞与少突胶质细胞祖细胞的分化受损（即OPC受损 分化），是MS神经系统进展的主要原因之一。再髓力促进疗法 与当前的免疫抑制药物相结合，代表了一种有希望的选择，用于治疗MS。 但是，很少有用于靶向髓鞘修复的药物。我们的长期目标是发现 治疗脱髓鞘性疾病的抗髓后促进策略。该提议的目的是 地址是否以及如何调节聚合物酶1（PARP1）如何调节OPC分化和髓鞘形成 并确定髓磷脂修复中PARP1介导的途径的治疗值。 PARP1是多方面的 在癌症生物学中已广泛审查的核蛋白质。激活后，PARP1催化 在其靶蛋白中共价添加聚（ADP-核糖）单位，这一过程称为parylation，可以是 由酶聚（ADP-核糖）糖醇（PARG）逆转。这是基础的临床原理 建议是活跃但不慢性MS病变中的寡头层谱系细胞显示出升高的PARP1 活动，表明PARP1可能是促进抗透明疗法的潜在靶标。但是，我们的 当前对寡头生物学和病理学中PARP1的知识极为有限，并且其治疗性 雷序列化的价值尚未确定。中心假设是PARP1通过其作用 酶活性是OPC分化和髓鞘化的固有双模型驱动器，可能是 利用以促进髓磷脂修复。我们的中心假设建立在概念和方法论之上 我们的基础是我们在体外和体内的遗传和药理操作的初步数据。这 假设将以三个特定目的进行检验：1）确定PARP1耗竭对OPC分化的影响 和髓鞘2）定义PARP1调节的OPC分化和髓鞘形成的机制； 3）确定PARP1介导的pary液对髓磷脂修复的损失和功能获得的影响。我们 通过采用我们实验室中产生的独特转基因模型来追求这三个目标。这 拟议的研究很重要，因为它将询问PARP1在髓磷脂修复中的治疗潜力 并为制定促进促进策略的概念基础。预期的结果将 具有重要的积极影响，因为他们将建立有关功能的第一概念图片 以及CNS髓磷脂形成和维修中PARP1的机制，它们将提供新的数据合理 介入PARP1介导的核化作为促进疗法的有前途的选择。