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

含缬洛新蛋白 (VCP) 的突变会导致一种罕见的复杂疾病，称为包涵体肌病 与佩吉特骨病和额颞叶痴呆（IBMPFD）有关。确切的底层 由突变VCP介导的分子和细胞致病和退行性机制仍然未知。 最近，肌萎缩侧索硬化症 (ALS) 患者也发现了 VCP 突变。 共同表明 VCP 生理功能的破坏会显着影响各种细胞 谱系和组织，这些变化可能是由共同的病理机制介导的。这有 是我们在神经退行性和肌肉退行性疾病方面长期目标的基本原理。 因此，建立这种复杂疾病的体外和体内模型是阐明这一复杂疾病的关键的第一步。 由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，并将 帮助开发针对这种破坏性疾病的潜在治疗策略。我们的初步数据以及 临床观察表明突变型 VCP 介导蛋白质降解过程受损 导致受影响细胞中蛋白质聚集体的积累。在这个提案中，我们假设 VCP 调节自噬和 .在目标 1 中，我们将研究潜在的分子机制 突变 VCP 损害细胞培养模型中的自噬，以及这些损害如何影响蛋白质 积累和先天炎症反应。在目标 2 中，我们将产生一种新型诱导转基因 携带 VCP 基因临床突变的小鼠作为 IBMPFD 模型。该转基因模型将 提供对疾病分子机制的深入了解，并将作为临床前的宝贵工具 治疗干预。可诱导的 VCP 小鼠模型对该领域具有重要意义，并提供 几个明显且显着的优点：（1）它只是 IBMPFD 的少数型号之一； (2)突变型VCP 表达不仅可以根据研究兴趣限制在特定组织，还可以开启 并在鼠标的使用寿命期间关闭； (3)通过限制突变体VCP的表达，我们能够避免 混淆并发症。我们相信，我们提出的项目将增进我们对以下方面的理解： IBMPFD 和相关的 VCP 疾病并有助于开发有效的疗法。

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.