Mechanisms underlying selective motor pool vulnerability in mouse and human SMA

小鼠和人类 SMA 选择性运动池脆弱性的机制

基本信息

批准号：
8526807
负责人：
Justin C Lee
金额：
$ 4.72万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-01-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8526807
关键词：
Address Affect Age Age-Years Agonist Alzheimer&apos s Disease Anatomy Area Atrophic Autopsy Blood - brain barrier anatomy Candidate Disease Gene Cell Nucleus Cells Cephalic Cessation of life Chest Childhood Cranial Nerves Denervation Disease Disease Resistance Dorsal Employee Strikes Exhibits Eye Movements Fiber Functional disorder Future Genes Genetic Glutamates Horns Human Hypertrophy Immunohistochemistry In Situ Hybridization Individual Intercostal Muscles Investigation Label Measures Metric Microarray Analysis Modeling Molecular Motor Motor Neuron Disease Motor Neurons Mus Muscle Nature Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurology Neuromuscular Diseases Neurons Outcome Measure Paralysed Parkinson Disease Pathology Pathway interactions Patients Pattern Pelvis Physiology Population Pre-Clinical Model Predictive Value Process Proteins RNA Regulation Relative (related person)Resistance Respiratory Diaphragm Respiratory Failure Role Shapes Skeletal muscle structure of neck Sphincter Spinal Spinal Cord Spinal Muscular Atrophy Staging Testing Therapeutic Time Translations Trigeminal System Ventral Roots Werdnig-Hoffmann Disease base burden of illness clinical phenotype functional disability human disease in vivo insight laser capture microdissection loss of function metabotropic glutamate receptor 8 mouse model neuromuscular neuron loss neuronal cell body neuroprotection new therapeutic target novel orbit muscle presynaptic public health relevance response survival motor neuron gene therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Selective loss of specific neuronal subsets is a universal feature of neurodegenerative diseases ranging, from Alzheimer's disease to Parkinson's disease. Although the nature of the disease trigger is only known for familial forms of disease, such triggers are in general expressed widely throughout the CNS. This raises a fundamental question in neurology: why do specific subsets of neurons degenerate in response to dysfunction of a ubiquitously expressed protein? Proximal spinal muscular atrophy (SMA) provides a unique opportunity to address these questions. SMA is a fatal neuromuscular disease characterized by differential loss of motor pools, anatomically discrete groups of motor neurons with a well-defined function - contraction of a single muscle in the periphery. For example, severe functional impairment of intercostal muscles in combination with functional sparing of the diaphragm produces a "bell-shaped" chest that is pathognomonic of SMA. Moreover, all patients with SMA have homozygous loss of function of the survival motor neuron (SMN) gene. Mouse models with loss of SMN are therefore representative of the disease in all patients. Studying selective motor pool vulnerability in SMA may uncover principles of selective neurodegeneration that can be applied to other disorders. This project aims to identify candidate therapeutic targets by identifying intrinsic molecular differences between vulnerable and resistant motor pools. Specifically, I will isolate RNA and perform transcriptional profiling on 12 differentially affected motor pools in SMA. These motor pools have diverse physiology, presynaptic connectivity, and wide anatomic distribution along the neuraxis. Therefore, I hypothesize that differentially expressed genes and pathways are promising candidates for contributing to disease resistance. I will manipulate these candidate genes in the SMN¿7 mouse model of SMA and assess for improvements in pathology, such as cell loss or neuromuscular denervation. Successful candidate genes represent promising targets for translation into human SMA and other neurodegenerative disorders that share common pathways. Future studies that focus on underlying mechanisms of neuroprotection may provide insight into principles of neurodegeneration broadly.

描述（由适用提供）：从阿尔茨海默氏病到帕金森氏病，特定神经元亚群的选择性丧失是神经退行性疾病的普遍特征。尽管该疾病触发的性质仅因疾病的家庭形式而闻名，但此类触发因素在整个中枢神经系统中通常都广泛表达。这就提出了神经病学的基本问题：为什么特定的神经元子集因响应无处不在表达的蛋白质功能障碍而退化？脊柱近端肌肉萎缩（SMA）为解决这些问题提供了独特的机会。 SMA是一种致命的神经肌肉疾病，其特征是运动池的差异，是分离的运动神经元的分离组，具有明确定义的功能 - 外周中单个肌肉的收缩。例如，肋间肌肉与隔膜的功能性保留相结合的严重功能障碍会产生一个“钟形”胸部，该胸部是SMA的病情。此外，所有SMA患者的生存运动神经元（SMN）基因的功能均质丧失。因此，SMN损失的小鼠模型代表所有患者的疾病。在SMA中研究选择性的运动池脆弱性可能会发现可以应用于其他疾病的选择性神经变性的原则。该项目旨在通过识别弱势运动池和抗性运动池之间的固有分子差异来识别候选治疗靶标。具体而言，我将隔离RNA并在12上进行转录分析 SMA中受差异影响的电动池。这些运动池具有沿神经毒素的潜水生理学，突触前连通性和较大的解剖分布。因此，我假设不同表达的基因和途径是有助于疾病抗性的候选者。我将在SMA的SMN小鼠模型中操纵这些候选基因，并评估病理学的改善，例如细胞丢失或神经肌肉神经神经化。成功的候选基因代表了转化为人类SMA和其他共同途径的神经退行性疾病的承诺靶标。侧重于神经保护的基本机制的未来研究可能会洞悉神经退行性的原理。