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.

项目摘要/摘要 与年龄有关的神经退行性疾病代表了社会的主要财务和情感燃烧，但迄今为止尚未 已经制定了预防策略。额颞痴呆（FTD）和肌萎缩性外侧硬化症（ALS）为 无情进行性疾病，涉及对行为和肌肉运动重要的神经元的变性， 分别。最近，在基因C9orf72的非蛋白质编码区域中的六核苷酸重复扩展为 被发现是FTD和ALS的最常见原因，占所有诊断的10％。两个盛行 已经提出了假设来解释这种突变如何导致神经元的逐渐丧失。功能的增益 （GOF）假设提议，即重复膨胀产生的毒性分子破坏神经功能并导致 他们的破坏。 C9orf72蛋白在 神经元功能和生存的支持，并且该基因的表达直接或间接地感知神经元 疾病。新证据表明，C9ORF72的小鼠直系同源物在免疫系统中起作用以限制 炎症和自身免疫性，尽管确切的机制需要进一步研究。该提议的第一个目标将 当C9orf72直系同源物减少并识别导致注射的途径和细胞类型 确定是否诱导了具有C9ORF72重复的人类的多能干细胞衍生的小胶质细胞样细胞 扩展显示相似的炎症表型。该提案的第二个目的旨在测试 通过将含有六核苷酸重复膨胀的病毒注射到表达的小鼠中，LOF假设在活生物体中 c9orf72直系同源物的正常或降低。如果较低的C9orf72直系同源动物对有毒的动物的水平较低 重复扩展的功能，这将为开发旨在提高水平的疗法提供支持 C9orf72或抑制其还原影响的途径。候选人将与潜水领域的专家一起培训 开发完成这些目标所需的技术技能并确定疾病相关的途径 在本提案的独立阶段追求。继续与候选人的顾问和专家进行培训 合作者将为他做好准备，以成功地实现一个独立研究小组的目标 所有级别的研究者和追求旨在了解神经退行性疾病病因的假设。