Core C

核心C

• 批准号: 10415045
• 负责人: Tania France Gendron
• 金额: $ 17万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415045
• 关键词: Address; Amyotrophic Lateral Sclerosis; Animals; Antisense Oligonucleotides; Autopsy; Behavior; Biochemical; Biochemical Genetics; Biological Markers; Biological Models; Brain; C9ORF72; Cerebrospinal Fluid; Clinic; Clinical; Clinical Research; Clinical Trials; Cognition; Collection; Data; Detection; Development; Diagnostic; Dipeptides; Disease; Disease Progression; Enrollment; Ensure; Evaluation; Genes; Genetic; Genotype; Harvest; Histopathology; Home; Human; Immunoassay; Immunohistochemistry; Individual; Induced pluripotent stem cell derived neurons; Investigation; Lead; Length; Life; Light; Link; Measures; Methods; Molecular; Mus; Muscle Weakness; Muscular Atrophy; Nerve Degeneration; Neurons; Nuclear Pore Complex Proteins; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Phenotype; Plasma; Play; Process; Production; Prognosis; Proteins; Proteome; Proteomics; RNA; Research Personnel; Research Project Grants; Resources; Role; Sampling; Series; Services; Spinal Cord; Testing; Therapeutic; Tissue Sample; Tissues; Translations; Treatment outcome; Validation; Western Blotting; Work; astrogliosis; base; bench to bedside; biomarker development; brain tissue; c9FTD/ALS; candidate marker; effective therapy; frontotemporal lobar dementia-amyotrophic lateral sclerosis; human tissue; improved; induced pluripotent stem cell; insight; mRNA Expression; member; neurofilament; new therapeutic target; novel marker; patient stratification; pharmacodynamic biomarker; protein TDP-43; success; survival prediction; targeted biomarker; therapeutic target; trait; transcriptome; transcriptomics; validation studies

PROJECT SUMMARY/ABSTRACT: CORE C G4C2 repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating diseases with no effective treatment. Success in developing a treatment for “c9ALS/FTD” will require a better understanding of disease pathomechanisms, the identification of molecular pathways amenable to therapeutic targeting, and the development of biomarkers to track disease progression and to confirm target engagement of potential therapies. The studies outlined in Projects 1, 2 and 3 aim to fill these needs, and the Human Validation Core (Core C) will work closely with Project investigators to facilitate these important studies. In addition to providing post-mortem tissues to Projects 1, 2 and 3, Core C will conduct a thorough neuropathological and biochemical analysis of these patient samples, including the quantification of TDP-43, P62 and dipeptide repeat (DPR) protein pathology, microgliosis and astrogliosis, and repeat length. Core C will similarly characterize brain tissues from (G4C2)149 mice used in Projects 1 and 3, and measure DPR protein levels in neurons differentiated from patient-derived induced pluripotent stem cells used in Project 2. These data will serve as valuable traits for the proteomic and transcriptomic studies conducted in all three projects to discover pathological mechanisms relevant to disease, and biomarkers for use in clinical trials. Furthermore, Core C will play a significant role in validating, at the protein level, expression changes of genes or proteins that associate with ALS genotypes or phenotypes, and that may define pathophysiological pathways linked to c9ALS. This will be done with independent methods of protein detection and using tissues from discovery series and validation series. Indeed, to ensure that the collection of post-mortem tissues from C9orf72 repeat expansion carriers continues to grow, Core C will work closely with Core B to obtain rapid autopsies of patients enrolled in clinical studies and provide diagnostic evaluations. In this fashion, we will further increase the number of patients from whom both antemortem cerebrospinal fluid (CSF) and postmortem brain tissue are available – important resources for comparing brain and CSF proteomes. With regards to the latter, Core C will help Project 3 home in on promising candidate biomarkers that warrant investigation in CSF, and assist in determining whether their top candidates could serve as CSF biomarkers for c9ALS/FTD.

项目摘要/摘要：核心C C9ORF72中的G4C2重复扩张是肌萎缩性侧索硬化症（ALS）最常见的遗传原因 和额颞痴呆（FTD），两种毁灭性疾病没有有效治疗。成功 开发“ C9ALS/FTD”的治疗方法将需要更好地了解疾病的病理，即 鉴定分子途径适合治疗靶向，以及生物标志物的发展 跟踪疾病进展并确认潜在疗法的目标参与。概述的研究 项目1、2和3旨在满足这些需求，人类验证核心（核心C）将与 项目研究人员促进这些重要研究。除了提供验尸时时间 项目1、2和3，Core C将对这些进行彻底的神经病理学和生化分析 患者样品，包括TDP-43，p62和二肽重复（DPR）蛋白质病理学的定量， 小胶质细胞增多和星形胶质细胞增多，重复长度。 Core C类似地表征了（G4C2）149的脑组织 项目1和3中使用的小鼠，并测量与患者衍生的神经元中的DPR蛋白水平 项目2中使用的诱导多能干细胞。这些数据将是蛋白质组学和 在所有三个项目中进行的转录组研究发现与疾病有关的病理机制， 和用于临床试验的生物标志物。此外，核心C将在验证中发挥重要作用， 蛋白质水平，与ALS基因型或表型相关的基因或蛋白质的表达变化，以及 这可能定义与C9AL有关的病理生理途径。这将通过独立的方法来完成 蛋白质检测并使用发现系列和验证系列的组织。确实，确保 C9ORF72重复扩展载体的验尸后组织的收集继续增长，Core C将有效 与核心B紧密接近以获得临床研究的患者的快速尸检并提供诊断 评估。以这种方式，我们将进一步增加二者anthertem的患者数量 可以使用脑脊液（CSF）和验尸后脑组织 - 比较大脑的重要资源 和CSF蛋白质组。关于后来，Core C将帮助Project 3 Home in Promise候选人 保证在CSF上进行投资的生物标志物，并协助确定他们的顶级候选人是否可以 用作C9ALS/FTD的CSF生物标志物。