Exploring Mechanisms of Pathogenicity in C9ORF72 Frontotemporal Dementia and Amyotrophic Lateral Sclerosis

探索C9ORF72额颞叶痴呆和肌萎缩侧索硬化症的致病机制

• 批准号: 10382565
• 负责人: Aaron Burberry
• 金额: $ 24.9万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382565
• 关键词: Accounting; Address; Affect; Age; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Anxiety; Autoimmunity; Behavior; Behavioral; Biochemical; Biological Models; Bone Marrow; Brain; C9ORF72; Cell Line; Cells; Cerebrospinal Fluid; Cessation of life; Chromosome 9; Cognitive; Development; Diagnosis; Dipeptides; Disease; Disease Outcome; Emotional; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Equilibrium; Etiology; Forelimb; Frontotemporal Dementia; Future; Gene Expression; Genes; Genetic; Goals; Hand Strength; Human; Image; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Initiator Codon; Introns; Lead; Learning; Linguistics; Measurement; Mentors; Methodology; Microglia; Modeling; Molecular; Motor; Motor Neurons; Movement; Mus; Muscle; Muscle function; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Neurophysiology - biologic function; Onset of illness; Organism; Orthologous Gene; Other Genetics; Paralysed; Pathogenicity; Pathology; Pathway interactions; Patients; Penetrance; Peripheral Nerves; Pharmacology; Phase; Phenotype; Play; Population; Predisposition; Prevention strategy; Production; Progressive Disease; Proteins; RNA; RNA metabolism; RNA-Binding Proteins; Reading Frames; Regulation; Research; Research Personnel; Role; Running; Skeletal Muscle; Social Interaction; Societies; Spinal; Spinal Cord; Stress; TNF gene; Technical Expertise; Testing; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Training; Transcript; Translating; United States; Virus; Visualization; age related neurodegeneration; behavior test; behavioral study; cell type; conditional knockout; frontotemporal lobar dementia-amyotrophic lateral sclerosis; gain of function; gene product; glial activation; improved functioning; in vitro Model; in vivo; induced pluripotent stem cell; insight; loss of function; loss of function mutation; macrophage; nerve supply; nervous system disorder; neuroinflammation; neuromechanism; neuromuscular; neuron loss; novel; pre-clinical; protein TDP-43; protein aggregation; protein biomarkers; relating to nervous system; response; sciatic nerve; screening; therapeutic candidate; therapy development; trafficking; trizol; vector

Project Summary/Abstract Age-related neurodegenerative disorders represent a major financial and emotional burden to society, but to date no preventative strategies have been developed. Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are relentlessly progressive diseases which involve the degeneration of neurons important for behavior and muscle movement, respectively. A hexanucleotide repeat expansion in a non-protein-coding region of the gene C9ORF72 was recently discovered to be the most common cause of FTD and ALS, responsible for 10% of all diagnoses. Two prevailing hypotheses have been suggested to explain how this mutation leads to progressive loss of neurons. The gain of function (GOF) hypothesis proposes that toxic molecules produced from the repeat expansion disrupt neural function and lead to their destruction. The loss of function (LOF) hypothesis proposes that the C9ORF72 protein plays an important role in support of neural function and survival and that reduced expression of this gene directly or indirectly sensitizes neurons to disease. New evidence indicates that the mouse ortholog of C9ORF72 functions in the immune system to limit inflammation and autoimmunity, although the exact mechanisms require further study. The first AIM of this proposal will be to identify pathways and cell types that contribute to inflammation when the C9ORF72 ortholog is reduced and to determine whether induced pluripotent stem cell-derived microglia-like cells from humans with the C9ORF72 repeat expansion display similar inflammatory phenotypes. The second AIM of this proposal seeks to test the validity of the LOF hypothesis in live organisms by injecting virus containing the hexanucleotide repeat expansion into mice that express normal or reduced levels of the C9ORF72 ortholog. If lower levels of the C9ORF72 ortholog sensitize animals to toxic features of the repeat expansion, this would provide support for developing therapies aimed at boosting levels of C9ORF72 or inhibiting pathways affected by its reduction. The candidate will train with experts in diverse fields to develop the technical skills necessary to complete these AIMs and to identify disease relevant pathways which can be pursued in the independent phase of this proposal. Continued training with the candidate’s advisor and expert collaborators will prepare him to succeed in his goal to run an independent research group in which he mentors investigators of all levels and pursues hypotheses aimed at understanding etiologies of neurodegenerative disease.

项目总结/摘要 与糖尿病相关的神经退行性疾病是社会的主要经济和情感负担，但迄今为止， 制定了预防战略。额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）是 无情地进行性疾病，涉及对行为和肌肉运动重要的神经元的变性， 分别最近，在C9 ORF 72基因的非蛋白质编码区的一个六核苷酸重复扩增被发现。 被发现是FTD和ALS最常见的原因，占所有诊断的10%。两个盛行 已经提出假说来解释这种突变如何导致神经元的进行性丧失。函数增益 (GOF)一种假说认为，重复扩增产生的有毒分子破坏了神经功能， 他们的毁灭。功能丧失（LOF）假说提出C9 ORF 72蛋白在细胞凋亡中起重要作用。 支持神经功能和存活以及该基因表达减少直接或间接地使神经元对 疾病新的证据表明，C9 ORF 72的小鼠直系同源物在免疫系统中起作用，以限制 炎症和自身免疫，但确切的机制需要进一步研究。该提案的第一个目标将 当C9 ORF 72直系同源物减少时，鉴定有助于炎症的途径和细胞类型， 确定来自人的具有C9 ORF 72重复序列的诱导多能干细胞衍生的小胶质细胞样细胞是否 扩增显示相似的炎性表型。本提案的第二个目的是测试 通过将含有六核苷酸重复扩增的病毒注射到小鼠体内， 正常或降低水平的C9 ORF 72直系同源物。如果较低水平的C9 ORF 72直向同源物使动物对毒性敏感， 重复扩增的特征，这将为开发旨在提高 C9 ORF 72或抑制受其减少影响的途径。候选人将与不同领域的专家一起培训， 发展必要的技术技能，以完成这些目标，并确定疾病相关的途径， 在本提案的独立阶段进行。与候选人的顾问和专家一起继续培训 合作者将为他成功实现经营一个独立研究小组的目标做好准备， 所有级别的研究人员和追求的假设，旨在了解神经退行性疾病的病因。