High-fat diet rescues lethality of homozygous knock-in R155H VCP myopathic mice

描述（由申请人提供）：我们的实验室是第一个确定VCP突变是遗传性包涵体肌病、骨Paget病、额颞叶痴呆和肌萎缩侧索硬化症的原因，并在确定这些疾病的潜在分子发病机制方面取得了进展。对患者成肌细胞和杂合子R155H小鼠的研究表明，VCP处于泛素-蛋白酶体信号通路和自噬通路的交叉点，这两种机制被认为是导致细胞内蛋白质降解和肌肉和大脑异常病理的原因。我们开发了首个携带常见R155H突变的敲入型VCP小鼠模型，该突变具有许多人类疾病的典型临床特征(1)。与R155H杂合子（VCPR155H/+）小鼠模型的疾病进展不同，纯合子（VCPR155H/R155H）具有更严重的肌肉、脑和脊髓病理，大多数存活时间不超过21天。结构和功能研究证明，纯合子表现出异常的自噬途径和线粒体增殖。最近的初步研究表明，给怀孕的杂合子母鸭喂食脂肪含量增加3%的饮食，可显著提高其纯合子后代的存活率。这些后代的寿命超过21天，并成功断奶，表明增加脂肪饮食改善了致死表型。在这个应用中，我们建议研究脂肪含量的最佳百分比，以进一步挽救致死表型。我们还将研究在正常和高脂肪饮食处理的纯合子VCP敲入小鼠中线粒体、自噬和泛素-蛋白酶体分子途径的重要改变。研究这一观察结果为VCP和相关疾病患者提供了一个有希望的治疗策略。

DESCRIPTION (provided by applicant): Our laboratory was the first to identify VCP mutations as a cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis, and has made progress in identifying the underlying molecular pathogenesis of these diseases. Studies of patients' myoblasts and the heterozygous R155H mouse have placed VCP at the intersection of the ubiquitin-proteasome signaling and autophagy pathways, both mechanisms being considered responsible for the intracellular protein degradation and abnormal pathology seen in muscle and brain. We have developed the first knock-in VCP mouse model carrying the common R155H mutation, which has many clinical features typical of the human disease (1). Unlike disease progression in the R155H heterozygous (VCPR155H/+) mouse model, homozygotes (VCPR155H/R155H) have a more severe muscle, brain and spinal cord pathology, with most surviving no more than 21 days. Homozygotes demonstrate an abnormal autophagic pathway and mitochondrial proliferation, as evidenced by structural and functional studies. Recent preliminary studies have shown that feeding pregnant heterozygous dams a diet with a 3% increase in fat results in a dramatic improvement in the survival of their homozygous offspring. These offspring live longer than 21 days and are successfully weaned, demonstrating that an increased fat diet ameliorates the lethal phenotype. In this application, we propose to investigate the optimum percentage of fat content on further rescuing the lethal phenotype. We will also study the important altered mitochondrial, autophagy and ubiquitin-proteasome molecular pathways in the homozygous VCP knock-in mice treated with normal versus high-fat diets. Studying this observation affords the opportunity to develop a promising therapeutic strategy for patients with VCP and related diseases.