Investigating Motor Neuron Disease in Spinocerebellar Ataxia, Type1

研究脊髓小脑共济失调 1 型运动神经元疾病

• 批准号: 10733124
• 负责人: James P Orengo
• 金额: $ 54.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733124
• 关键词: Abnormal coordination; Address; Affect; Area; Ataxia; Behavioral; Behavioral Assay; Brain Stem; Breathing; CAG repeat; Cell Culture Techniques; Cell Nucleus; Cells; Cerebellar degeneration; Cessation of life; Deglutition; Denervation; Development; Disease; Disease Progression; Dissociation; Electrophysiology (science); Family; Functional disorder; Genetic Epistasis; Genetic Transcription; Goals; Health; Histology; Impairment; Individual; Intervention; Investigation; Investments; JUN gene; Knowledge; Lead; Life; LoxP-flanked allele; MAPK8 gene; Mediating; Modeling; Molecular; Morphology; Motor Neuron Disease; Motor Neurons; Mus; Muscle Weakness; Muscular Atrophy; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neuronal Dysfunction; Neurons; Nuclear; Pathogenicity; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Phosphotransferases; Play; Process; Proteins; Respiration Disorders; Respiratory Failure; Risk; Role; Secondary to; Shortness of Breath; Signal Transduction; Skeletal Muscle; Sorting; Spinal Cord; Spinocerebellar Ataxias; Symptoms; Tissues; Type 1 Spinocerebellar Ataxia; astrogliosis; behavioral phenotyping; brain cell; cell type; deep sequencing; effective therapy; experimental study; in vivo; inhibitor; innovation; interest; mRNA sequencing; motor neuron degeneration; mouse model; neuron loss; neuronal cell body; novel; novel therapeutics; overexpression; polyglutamine; premature; respiratory; response; skeletal muscle wasting; transcriptome sequencing; transcriptomics

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia due to cerebellar degeneration, followed by progressive degeneration and premature death. Substantial effort has been invested in determining the molecular mechanisms that lead to cerebellar degeneration. This is largely due to the fact that impairment of these neurons leads to the first symptoms identified in SCA1 patients. However, loss of cerebellar neurons alone does not account for the muscle weakness and respiratory failure, which characterize SCA1 progression, and promote premature death. This knowledge gap prompts fundamental questions about the pathogenic mechanism of premature death. SCA1 is caused by the expansion of CAG repeats encoding polyglutamines (polyQ) in the ATAXIN1 (ATXN1) protein. The polyQ ATXN1 accumulates in neurons forming nuclear aggregates ultimately leading to neuronal cell death. Of particular interest to the Orengo lab is the role motor neurons play in SCA1. These neurons control skeletal muscle activity, and when diseased, lead to skeletal muscle wasting, weakness, breathing dysfunction, swallowing difficulties and an inability to safely clear the airway, all of which predispose to respiratory complications leading to premature death. Dr. Orengo and his team hypothesize that motor neuron dysfunction in SCA1 is the main driver of premature death and that the mechanisms leading to motor neuron degeneration in SCA1 are different than those involved in cerebellar neuron degeneration. This distinction may be critical in the development of novel therapeutics that address other affected cell types than just cerebellar neurons. Using a cadre of SCA1 mouse models, the Orengo lab will be able to selectively turn on or off the expression of toxic polyQ ATXN1 in motor neurons and assess the molecular and behavioral changes that follow. Specifically, the goals of this proposal are the following. (1) Assess whether expression of polyQ ATXN1 in motor neurons is necessary for premature death in a conditional mouse model of SCA1. (2) Determine the earliest, mid and late transcriptomic changes in motor neurons secondary to autonomous and non-cell-autonomous polyQ ATXN1 expression. This investigation utilizes an innovative in vivo approach, with dissociated motor neurons from the spinal cords of mice, sorting their nuclei based on a fluorescent marker, and then deep sequencing the mRNA molecules present. (3) Explore the role of the master transcriptional regulator Mdfi in a SCA1 mouse model and ascertain its affect upon the JNK/Jun signaling cascade. Dr. Orengo’s proposed study is significant because it will shed new light on the role motor neuron disease plays in SCA1, as well as what pathways are triggered within these neurons that lead to their degeneration. Understanding these mechanisms will be crucial for developing more effective therapies that address muscle weakness and premature death in SCA1 patients.

1型脊髓脑性共济失调（SCA1）是一种毁灭性的神经退行性疾病，其特征是进行性疾病 小脑变性引起的共济失调，然后进行性变性和过早死亡。重大的 已经投入了努力来确定导致小脑变性的分子机制。这是 很大程度上是由于这些神经元的损伤导致SCA1患者发现的第一个症状。 但是，仅小脑神经元的丧失并不能说明肌肉无力和呼吸衰竭， 这是SCA1进展的特征，并促进过早死亡。这种知识差距促使基本 关于过早死亡的致病机制的问题。 SCA1是由CAG的扩展引起的 重复编码Ataxin1（ATXN1）蛋白质中的聚谷氨酰胺（PolyQ）。 polyq atxn1积累 形成核骨料的神经元最终导致神经元细胞死亡。 Orengo特别感兴趣 实验室是运动神经元在SCA1中扮演的角色。这些神经元控制骨骼肌活动，并且患病时， 导致骨骼肌肉浪费，无力，呼吸功能障碍，吞咽困难和无法安全的 清除呼吸道，所有这些气道易于呼吸并发症，导致过早死亡。 Orengo博士 他的团队假设SCA1中的运动神经元功能障碍是过早死亡的主要驱动力，并且 导致SCA1运动神经元变性的机制与参与小脑的机制不同 神经元变性。这种区别在开发新疗法的发展中可能至关重要 受影响的细胞类型不仅是小脑神经元。使用SCA1鼠标的干部，Orengo Lab将是 可以选择性地打开或关闭运动神经元中有毒Polyq ATXN1的表达并评估分子 和随后的行为变化。具体而言，该提案的目标如下。 （1）评估是否 在有条件的小鼠模型中，在运动神经元中PolyQ ATXN1在运动神经元中的表达是必要的 SCA1。 （2）确定继发于运动神经元的最早，中期和晚期的转录组变化 自主和非细胞自主polyq atxn1表达。这项投资利用了体内创新的 接近小鼠脊髓分离的运动神经元，将其核基于A排序 荧光标记物，然后对存在的mRNA分子进行深层测序。 （3）探索主人的角色 SCA1鼠标模型中的转录调节器MDFI并确定其对JNK/JUN信号的影响 级联。 Orengo博士的拟议研究很重要，因为它将对运动神经元的角色发明新的启示 疾病在SCA1中发挥作用，以及在这些神经元中触发的途径，导致它们 退化。了解这些机制对于开发更有效的疗法至关重要 解决SCA1患者的肌肉无力和过早死亡。