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

包含Valosin蛋白(VCP)的突变导致一种罕见的复杂疾病，称为包涵体肌病 与Paget病相关的骨性和额颞部痴呆(IBMPFD)。确切的潜在原因 突变型VCP介导的分子和细胞致病及退变机制尚不清楚。 最近，在肌萎缩侧索硬化症(ALS)患者中也发现了VCP突变。 共同表明，VCP生理功能的紊乱显著影响了各种细胞 血统和组织，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理论基础。 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。 由疾病相关突变VCP和Will触发的细胞和分子基础的致病过程 帮助开发这种毁灭性疾病的潜在治疗策略。我们的初步数据以及 临床观察提示，突变的VCP介导了蛋白质降解过程的损害和 导致蛋白质聚集物在受影响的细胞中积累。在本提案中，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， 突变的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 积聚和先天的炎症反应。在目标2中，我们将产生一种新的可诱导转基因 存在VCP基因临床突变的小鼠作为IBMPFD的模型。这个转基因模型将 提供对疾病分子机制的洞察，并将作为临床前研究的宝贵工具 治疗性干预。可诱导的VCP小鼠模型在该领域具有重要意义，并提供了 几个明显而显著的优点：(1)它只是IBMPFD的少数模型之一；(2)突变的VCP 基于研究兴趣，表达不仅可以局限于特定组织(S)，还可以被打开 以及(3)通过限制突变的VCP表达，我们能够避免 令人困惑的复杂情况。我们相信，我们提出的项目将增进我们对 IBMPFD和相关的VCP疾病，并帮助开发有效的治疗方法。

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.