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Dissecting the in vivo role of Huntingtin in Rab vesicle movement on microtubules

剖析亨廷顿蛋白在微管上 Rab 囊泡运动中的体内作用

基本信息

批准号：
8721495
负责人：
Shermali Gunawardena
金额：
$ 7.73万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
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：
2013-08-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721495
关键词：
Actins Affect Axon Axonal Transport Binding Brain Diseases Caliber Cell Death Chorea Clathrin Complex Corpus striatum structure Cytoplasmic Inclusion Cytoskeleton Defect Development Disease Disease Pathway Drosophila genus DsRed Dynein ATPase Endocytosis Endosomes Event FDA approved Genetic Gliosis Goals Health Human Huntington Disease Impaired cognition Inherited Intracellular Transport Investigation Kinesin Knowledge Life Mediating Membrane Protein Traffic Microtubule Proteins Microtubules Mission Motor Movement Mus Nerve Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Inclusion Organism Orthologous Gene Outcome Pathology Pathway interactions Physiological Play Preventive Intervention Proteins Public Health Recycling Regulation Research Role Symptoms Testing Therapeutic Therapeutic Intervention Transport Vesicles Vesicle Work base burden of illness cell motility disability effective therapy end stage disease genetic analysis human Huntingtin protein in vivo innovation loss of function mutant neuron loss neuropathology novel prevent public health relevance

项目摘要

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating, dominantly inherited neurodegenerative disease clinically characterized by chorea and cognitive impairment due to loss of striatal neurons. Currently there are no effective treatments/cures for HD. Most therapeutic treatments currently used are aimed at dissolving/dissociating aggregates and preventing cell death, common neuropathology seen at the end stage of disease. Although the HD protein, huntingtin (HTT) is critical for viability, the complexity of HTT-mediated associations indicates multiple functions. Thus the challenge is to unravel the primary function of HTT, which when disrupted initiates disease. Previous work put forth a tantalizing proposal that disruption of axonal transport within long, narrow-caliber axons is an early event that causes protein accumulations that elicit cell death, ultimately resulting in neuronal dysfunction observed in HD. Our long-term goal is to understand how HTT-mediated axonal transport defects initiate disease pathways. The objective here, which is our next step in the pursuit of thi goal, is to determine how HTT influences the transport of a specific sub class of vesicles (Rab proteins). Our central hypothesis is that disruption of Rab vesicle transport within axons mediated by HTT can contribute to early neuropathology observed in HD. There are two clear predictions of this hypothesis; 1: HTT and Rab proteins are on the same vesicles and 2: Rab vesicles use kinesin-1 and dynein motors for movement on microtubules (MT). In this context our specific aim is to identify how HTT influences Rab proteins for MT-dependent transport within axons. We have 5 specific objectives, 1: determine how HTT influences Rab proteins, 2: test the prediction that HTT and Rab11, Rab32 and RabX4 are on the same vesicle, 3: test the prediction that Rab32 and RabX4 are both on the Rab11 vesicle, 4: test the prediction that Rab32 and RabX4 use kinesin-1 and dynein motors for movement on MT, and 5: test the prediction that mutant HTT disrupts Rab-mediated functions. A comprehensive in vivo approach will be used to dissect the physiological role of HTT in Rab vesicle transport in an organism. The rationale for the proposed research is that once the mechanisms of how HD disease is initiated by perturbations in Rab transport by mutant HTT are known, new and innovative approaches against HD can be developed. Therefore identifying how HTT normally functions in neurons will have a significant impact on providing novel target pathways for developing effective preventive and therapeutic interventions, which are currently unavailable for HD. Thus our work is innovative, in our opinion because it represents a new and substantive departure from the status quo, namely the approach of detailing the role of HTT using in vivo dynamics of vesicle movement in a living organism. The proposed research is significant, because it is expected to vertically advance and expand our understanding of how disease pathways initiate, which will significantly alter current knowledge. The knowledge acquired will dramatically propel the development of numerous pharmacological or genetic modifiers against axonal defects or to restore Rab function.

描述（由申请人提供）：亨廷顿病（HD）是一种毁灭性的显性遗传性神经退行性疾病，临床特征为由于纹状体神经元缺失导致的舞蹈病和认知障碍。目前尚无有效的治疗方法。目前使用的大多数治疗性治疗旨在溶解/解离聚集体并防止细胞死亡，这是在疾病末期观察到的常见神经病理学。虽然HD蛋白，亨廷顿蛋白（HTT）是至关重要的生存能力，HTT介导的协会的复杂性表明多种功能。因此，挑战在于解开HTT的主要功能，当HTT被破坏时，它会引发疾病。以前的工作提出了一个诱人的建议，即长，窄口径轴突内的轴突运输中断是一个早期事件，导致蛋白质积累，引起细胞死亡，最终导致在HD中观察到的神经元功能障碍。我们的长期目标是了解HTT介导的轴突运输缺陷如何启动疾病途径。这里的目标，这是我们追求这一目标的下一步，是确定HTT如何影响一个特定的小泡（Rab蛋白）的运输。我们的中心假设是，在轴突内的Rab囊泡运输中断HTT介导的，可以有助于早期神经病理学观察HD。这个假说有两个明确的预测：1：HTT和Rab蛋白在相同的囊泡上，2：Rab囊泡使用驱动蛋白-1和动力蛋白马达在微管（MT）上运动。在这种情况下，我们的具体目标是确定HTT如何影响Rab蛋白在轴突内的MT依赖性运输。我们有5个具体目标，1：确定HTT如何影响Rab蛋白，2：测试HTT和Rab 11、Rab 32和RabX 4在同一囊泡上的预测，3：测试Rab 32和RabX 4都在Rab 11囊泡上的预测，4：测试Rab 32和RabX 4使用驱动蛋白-1和动力蛋白马达在MT上运动的预测，以及5：测试突变HTT破坏Rab-mediated功能的预测。一个全面的体内方法将被用来解剖的生理作用，HTT在Rab囊泡运输在一个有机体。拟议研究的基本原理是，一旦HD疾病是如何通过突变HTT引起的Rab转运的扰动而引发的机制已知，就可以开发新的和创新的方法来对抗HD。因此，确定HTT如何在神经元中正常发挥作用将对提供新的靶向途径以开发有效的预防和治疗干预措施产生重大影响，这些干预措施目前无法用于HD。因此，我们的工作是创新的，在我们看来，因为它代表了一个新的和实质性的偏离现状，即详细说明HTT的作用，在活的生物体中使用囊泡运动的体内动力学的方法。这项拟议中的研究意义重大，因为它有望纵向推进和扩大我们对疾病途径如何启动的理解，这将显著改变现有的知识。所获得的知识将极大地推动许多针对轴突缺陷或恢复Rab功能的药理学或遗传修饰剂的开发。