Pathogenic role of valosin-containing protein (VCP) in IBMPFD

含缬洛辛蛋白 (VCP) 在 IBMPFD 中的致病作用

基本信息

批准号：
8660646
负责人：
Masashi Kitazawa
金额：
$ 23.35万
依托单位：
UNIVERSITY OF CALIFORNIA, MERCED
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-09 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660646
关键词：
Affect Aging Amyotrophic Lateral Sclerosis Animal Model Area Autophagocytosis Behavioral Biochemical Brain Cell Culture Techniques Cell Line Cell Lineage Cell Proliferation Cell Survival Cells Cellular Stress Response Characteristics Clinical Clinical Data Cognitive Complex DNA-Binding Proteins Data Degenerative Disorder Dementia Development Disease Disease model Distal Frontotemporal Dementia Generations Genes Histopathology Human Impairment In Vitro Inclusion Bodies Inflammation Inflammatory Response Inflammatory Response Pathway Knowledge Lead Longevity Mediating Mentors Modeling Molecular Mus Muscle Muscular Dystrophies Mutation Myoblasts Myopathy Nerve Degeneration Neurologic Osteitis Deformans Paget&apos s Disease Pathology Patients Phase Phenotype Physiological Plant Roots Postdoctoral Fellow Process Proteins Research Role Skeletal Muscle Techniques Testing Therapeutic Therapeutic Intervention Tissues Transgenic Mice Transgenic Model Ubiquitin base bone effective therapy in vitro Model in vivo in vivo Model insight interest loss of function monocyte mouse model mutant neuroblast novel pre-clinical protein TDP-43 protein aggregate protein degradation protein expression response tool valosin-containing protein

项目摘要

Mutations in valosin-containing prote in (VCP) cause a rare complex disorder called inclusion body myopathy associated with Paget disease ofthe bone and frontotemporal dementia (IBMPFD). The exact underlying molecular and cellular pathogenic a nd degenerative mechanisms mediated by mutant VCP remain unl<nown. Quite recently, mutations in VCP have also been found patients in amyotrophic lateral sclerosis (ALS). collectively suggesting that dysruptions of physiological functions of VCP significantly impact various cell lineages and tissues, and these changes may be mediated by shared pathological mechanisms. This has been the rationale for our longstanding objective in neurodegenerative and muscular degenerative disorders. Therefore, establishing in vitro and in vivo models ofthis complex disease is a critical first step for elucidating the cellular- and molecular-based pathogenic processes triggered by a disease-relevant mutant VCP and will help developing potential therapeutic strategies for this devastating disorder. Our preliminary data as well as clinical observations suggest mutant VCP mediates an impairment of protein degradation processes and results in accumulations of protein aggregates in affected cells. In this proposal, we hypothesize that VCP regulates autophagy and . In Aim 1, we will investigate the underlying molecular mechanisms by which mutant VCP impairs autophagy in cell culture models, and how these impairments impact on protein accumulations and innate inflammatory responses. In Aim 2, we will generate a novel induci ble transgenic mouse harboring a clinical mutation in the VCP gene as a model for IBMPFD. This transgenic model will provide insight into the m olecular mechanisms of the disease, and will serve as a valuable tool for preclinical therapeutic interventions. The inducible VCP mouse model is significant for the field and offers several distinct and significant advantages: (1) it is only one of a few models for IBMPFD; (2) mutant VCP expression can not only be limited to specific tissue(s) based on the research interest, but also be turn on and off during the lifespan of the mouse; and (3) by limiting mutant VCP expression, we are able to avoid confounding complications. We believe that our proposed pr eject will advance our understandin gs in IBMPFD and related VCP diseases and help developing effective therapies.

（VCP）中含瓣膜蛋白蛋白的突变会导致一种罕见的复杂疾病，称为包容体肌病与骨骼和额颞痴呆（IBMPFD）的Paget疾病有关。确切的基础突变体VCP介导的分子和细胞致病性和退化机制仍然不<nown。最近，还发现了VCP中的突变患者肌萎缩性侧索硬化症（ALS）。共同提出VCP生理功能的失调会显着影响各种细胞谱系和组织，这些变化可以通过共同的病理机制介导。这就是一直是我们长期存在神经退行性和肌肉退行性疾病的基本原理。因此，建立这种复杂疾病的体外和体内模型是阐明的关键第一步与疾病相关的突变体VCP触发的基于细胞和分子的致病过程，将会帮助制定这种毁灭性疾病的潜在治疗策略。我们的初步数据以及临床观察结果表明，突变体VCP介导了蛋白质降解过程的损害和导致受影响细胞中蛋白质聚集体的积累。在此提案中，我们假设VCP 调节自噬和。在AIM 1中，我们将研究基本的分子机制突变体VCP会损害细胞培养模型中的自噬，以及这些损伤如何影响蛋白质积累和先天的炎症反应。在AIM 2中，我们将产生一种新颖的诱导型转基因小鼠在VCP基因中具有临床突变为IBMPFD的模型。这个转基因模型将提供有关该疾病的卵巢机制的洞察力，并将作为临床前的有价值工具治疗干预措施。可诱导的VCP鼠标模型对于该领域很重要，并且提供几个独特而显着的优势：（1）它只是IBMPFD的几个模型之一；（2）突变体VCP 表达不仅可以根据研究兴趣限于特定的组织，而且可以打开在老鼠的寿命中关闭；（3）通过限制突变体VCP表达，我们能够避免混淆并发症。我们认为，我们提议的公关将推进我们的理解 IBMPFD和相关的VCP疾病，并有助于开发有效的疗法。