Phenotyping Corticospinal Axon Degeneration in Preclinical ALS Models.

临床前 ALS 模型中皮质脊髓轴突变性的表型分析。

• 批准号: 10732637
• 负责人: Eric F Schmidt
• 金额: $ 46.61万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732637
• 关键词: ALS patients; Affinity Chromatography; American; Amyotrophic Lateral Sclerosis; Anatomy; Animal Model; Atrophic; Axon; Axonal Transport; Binding; Biochemical; Bioenergetics; Bioinformatics; Brain; Brain Stem; Cell Death; Cell physiology; Cells; Cerebral cortex; Cessation of life; Chromosome Mapping; Cicatrix; Clinical; Cortical Cord; Corticospinal Tracts; Data; Dendrites; Dependovirus; Detection; Diagnosis; Disease; Disease Progression; Disease model; Fiber; Foundations; Functional disorder; Future; Gene Expression; Genes; Genetic; Grant; Histologic; Human; Knowledge; Label; Link; Maps; Measures; Mediating; Messenger RNA; Metabolic; Methods; Mitochondria; Modeling; Molecular; Monitor; Motor Cortex; Motor Neuron Disease; Motor Neurons; Movement; Mus; Mutation; Nerve Degeneration; Neurons; Onset of illness; Paralysed; Pathologic Processes; Pathology; Pathway interactions; Patients; Phenotype; Polyribosomes; Population; Pre-Clinical Model; Presynaptic Terminals; Property; Proteomics; Pyramidal Cells; RNA purification; Reporter; Reproducibility; Research; Ribosomal Proteins; Ribosomes; Role; Severities; Spinal; Spinal Cord; Structure; Synapses; Techniques; Therapeutic; Thinness; Time; Transcript; Translating; Vertebral column; Viral; Viral Vector; Work; axonal degeneration; cell cortex; cell type; differential expression; disease prognosis; disease-causing mutation; excitotoxicity; experimental study; gene repression; in vivo; innovation; motor symptom; mouse model; neuron loss; neuronal cell body; novel; novel strategies; postsynaptic; pre-clinical; preclinical study; superoxide dismutase 1; synaptic function; transcriptome sequencing

Over 30,000 Americans currently suffer from amyotrophic lateral sclerosis (ALS) which is characterized by progressive paralysis due to the degeneration of nerve cells in the brain and spinal cord that control movement. Almost all cases of ALS are eventually fatal, and the rapid progression of the disease makes it particularly devastating, with most deaths occurring 2-5 years from diagnosis. No cure exists for ALS and the only available treatments slow disease progression by merely a few months Therefore, a great need exists for more effective and specific therapies that can stop or even reverse neurodegeneration. Innovation for such therapies will only arise from a better understanding of the molecular and cellular mechanisms underlying the pathological process. Degeneration of the “upper” motor neurons (UMNs) in the cerebral cortex that project to the spinal cord is an important hallmark of ALS and a cortical indication is required for diagnosis. The severity of cortical pathology also correlates with disease progression and prognosis. Because UMNs are difficult to distinguish from other cortical cell types they are often overlooked in preclinical studies. Therefore, properties that make them vulnerable to disease-causing mutations and the mechanisms that underlie their degeneration have remained a mystery. The proposed study aims to overcome this by utilizing cutting edge molecular, cellular, and anatomical techniques to interrogate neurodegenerative mechanisms in UMNs during disease progression. Specifically, this project will focus on the local pathology of the axons of UMNs in the spinal cord. Loss of these fibers is an early phenomenon of ALS and is characterized by a thinning and scarring of the corticospinal tract (CST) and may be a triggering factor for disease onset. Abnormalities in CST axons have also been observed at early time points in preclinical animal models, often preceding UMN loss. This grant will utilize a common mouse model of ALS that utilizes disease-linked mutations in the SOD1 gene (SOD1G93A) and recapitulates the neurodegeneration seen in human patients. In Aim 1, advanced viral tracing techniques will be used to label the neurons in the mouse spinal cord that receive direct synaptic input from UMNs and map changes in connectivity during disease progression. In parallel, the translating ribosome affinity purification (TRAP) method will be used in Aim 2 to monitor changes in the genes that are locally expressed in the axons. Aim 3 will examine the bioenergetic properties of the axons by employing a novel approach to isolate axonal mitochondria in order to perform biochemical and metabolic analyses during disease progression. This exploratory study will be the first to directly correlate changes in anatomy, gene expression, and bioenergetics specifically in degenerating axons, therefore laying a foundation for future work investigating mechanisms of CST pathology.

目前有超过30,000名美国人患有肌萎缩侧索硬化症（ALS），其特征是