Using genetic approaches to explore the role of group I PAKs in developmental myelination of the mammalian CNS

使用遗传方法探索 I 组 PAK 在哺乳动物 CNS 发育髓鞘形成中的作用

• 批准号: 10528035
• 负责人: Fuzheng Guo
• 金额: $ 43.93万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528035
• 关键词: Actins; Affect; Anatomy; Axon; Biohazardous Substance; Brain; Budgets; Cell Lineage; Cells; Child; Clinical; Clinical Data; Clinical Research; Cytoskeleton; Data; Data Analyses; Data Compromising; Defect; Development; Embryo; Exhibits; Exploratory/Developmental Grant; Family; Future; Gene Expression; Genetic; Impairment; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Macrocephaly; Magnetic Resonance Imaging; Mediating; Molecular; Morphology; Mus; Mutant Strains Mice; Mutate; Mutation; Myelin; Neuraxis; Neurologic; Neurons; Nonsense Mutation; Oligodendroglia; Outcome; Patients; Phosphotransferases; Pilot Projects; Play; Protein-Serine-Threonine Kinases; Proteins; Public Health; Reporting; Rodent Model; Role; Subgroup; Suggestion; Synapses; Terminator Codon; Tertiary Protein Structure; Testing; Vertebrates; White Matter Hyperintensity; Zebrafish; affective disturbance; animal data; autism spectrum disorder; autistic; base; cdc42 GTP-Binding Protein; cohort; conditional knockout; gain of function; gain of function mutation; genetic approach; human subject; in vivo; inhibitor; knock-down; knockout animal; loss of function; member; mouse genetics; mouse model; myelination; nervous system development; neurodevelopment; neuron development; p21 activated kinase; postnatal; screening; white matter

Using genetic approaches to explore the role of group I PAKs in developmental myelination of the mammalian CNS This project aims to interrogate if and how group I p21(Cdc42/Rac1)-activated kinases (PAKs), a family of serine/threonine kinases, regulate developmental myelination in the mammalian central nervous system (CNS). Group I PAKs (PAK1-3) have unique and different activating mechanism from that of group II PAKs (PAK4-6) and is the focus of the project. Despite sharing the common activating mechanism, PAK1 and, to a lesser extent, PAK2, are highly expressed in oligodendroglial lineage cells and are therefore the focuses of this application whereas PAK3 is primarily enriched in neurons. PAK1 and PAK2 are found to be mutated in human subjects. Clinical studies have shown that kinase gain-of-function mutations of PAK1, the founding members of PAKs, are associated with neurodevelopmental abnormalities, macrocephaly, and white matter anomalies and hypomyelination in affected children while PAK2 nonsense mutation (loss-of-function) is reported in patients with autism which display abnormalities of neurodevelopment and hypermyelination in the brain. Previous studies during the past two decades have established that group I PAKs play crucial roles in regulating neuronal development and function. However, the role of group I PAKs, particularly the oligodendroglial- enriched PAK1 and PAK2, in CNS developmental myelination remains enigmatic. In this exploratory project, we plan to define the role of PAK1/2 in oligodendrocyte development and developmental myelination in the mammalian CNS by leveraging mouse genetics. We will conditionally disrupt PAK1/2 or inhibit PAK1/2 catalytic activity in oligodendroglial lineage cells and assess the outcomes in developmental myelination. We will also explore how PAK1/2 regulates oligodendroglial development. The overall impact of this project is that it will provide the first in vivo evidence defining the causative role of PAK1/PAK2 mutations in clinically observed myelination disturbance in the mammalian CNS and will spark future studies screening and interrogating the role of PAK1/PAK2-regulated downstream targets in CNS developmental myelination.

使用遗传方法来探索I组在发育中的作用 哺乳动物CNS 该项目旨在询问IG和如何组I P21（CDC42/RAC1）激活激酶（PAKS），一个家庭 丝氨酸/苏氨酸激酶，调节哺乳动物中枢神经系统中的发育性髓鞘化 （CNS）。 I组PAKS（PAK1-3）具有与II组PAK的独特且不同的激活机制 （PAK4-6），是项目的重点。尽管共享了共同的激活机制，但PAK1和 较小的PAK2在寡头谱系细胞中高度表达，因此是这种重点 施用，而PAK3主要富含神经元。发现PAK1和PAK2在人类中被突变 主题。临床研究表明，激酶的功能收益突变是Pak1的创始成员 paks与神经发育异常，脑头畸形和白质异常有关，并且 患者的PAK2胡说八道突变（功能丧失）的患者中的低切髓性 自闭症在大脑中表现出神经发育和过度分泌的异常。以前的 在过去的二十年中，研究确定了I组在调节中起着至关重要的作用 神经元的发育和功能。但是，第一组的作用，尤其是寡头 - 中枢神经系统发育性髓鞘中富集的PAK1和PAK2仍然神秘。在这个探索性项目中 我们计划定义PAK1/2在少突胶质细胞发育和发育性髓鞘中的作用 哺乳动物CNS通过利用小鼠遗传学。我们将有条件破坏PAK1/2或抑制PAK1/2 少突胶质谱系细胞中的催化活性，并评估发育髓鞘的结果。我们 还将探讨PAK1/2如何调节寡头的发展。该项目的总体影响是 它将提供第一个定义PAK1/PAK2突变在临床上的病因作用的体内证据 观察到哺乳动物中枢神经系统中的髓鞘紊乱，并将引发未来的研究筛查和 询问PAK1/PAK2调节的下游靶标在CNS发育髓鞘中的作用。