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

基本信息

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
项目类别：
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

项目摘要

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 在中枢神经系统髓磷脂形成和修复中的奇特案例目前的抗炎药物可以减少免疫攻击，但不能有效预防神经系统疾病多发性硬化症 (MS) 的进展，这是最常见的中枢神经系统脱髓鞘疾病（中枢神经系统）无法治愈，影响了美国约 400,000 人。髓鞘再生失败，主要是由于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。促进髓鞘再生治疗与目前的免疫抑制药物联合治疗多发性硬化症是一种有前景的选择。然而，很少有药物可用于靶向髓磷脂修复。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。该提案的目的是探讨聚（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 介导的通路在髓磷脂修复中的治疗价值。 PARP1 是一个多方面的核蛋白已在癌症生物学中得到广泛研究。 PARP1 激活后会催化将聚（ADP-核糖）单元共价添加到其靶蛋白上，这一过程称为 PARylation，可以被聚（ADP-核糖）糖水解酶（PARG）逆转。这背后的临床原理提议认为，活动性而非慢性多发性硬化症病变中的少突胶质细胞谱系细胞显示 PARP1 升高活性，表明 PARP1 可能是促进髓鞘再生治疗的潜在靶标。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，其治疗作用髓鞘再生的价值尚未确定。中心假设是 PARP1 通过其作用酶活性是 OPC 分化和髓鞘形成的内在双模型驱动因素，可能是用于促进髓磷脂修复。我们的中心假设建立在概念和方法论的基础上我们的体外和体内遗传和药理学操作的初步数据奠定了基础。这假设将在三个具体目标上进行检验：1) 确定 PARP1 耗竭对 OPC 分化的影响和髓鞘形成； 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 PARylation 的功能丧失和获得对髓磷脂修复的影响。我们将通过采用我们实验室生成的独特转基因模型来实现这三个目标。这拟议的研究意义重大，因为它将探讨 PARP1 在髓磷脂修复中的治疗潜力并为制定促进髓鞘再生策略奠定概念基础。预期成果将具有重要的积极影响，因为他们将建立有关该功能的第一个概念图以及 PARP1 在中枢神经系统髓磷脂形成和修复中的机制，它们将提供新的数据证明干预 PARP1 介导的 PARylation 作为促进髓鞘再生治疗的一个有前途的选择。