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

高脂肪饮食挽救纯合敲入 R155H VCP 肌病小鼠的致死率

基本信息

批准号：
8534709
负责人：
VIRGINIA Eunice KIMONIS
金额：
$ 17.65万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534709
关键词：
Amyotrophic Lateral Sclerosis Animal Model Animals Autophagocytosis Autophagosome Biochemical Brain Clinical Coconut Oil Development Diet Disease Disease Progression Exhibits Fatty Acids Fatty acid glycerol esters Frontotemporal Dementia Genes Heterozygote Homozygote Human Inclusion Bodies Inherited Knock-in Mouse Laboratories Life Methods Mitochondria Modeling Molecular Monitor Mus Muscle Muscle Weakness Mutation Myoblasts Myocardium Myopathy Osteitis Deformans Pathogenesis Pathology Pathway interactions Patients Phenotype Reporting Signal Pathway Signal Transduction Source Spinal Cord System Testing Therapeutic Ubiquitin Weaning Weight disease phenotype feeding human disease mitochondrial autophagy mouse model multicatalytic endopeptidase complex muscle strength novel offspring preclinical study pregnant protein degradation public health relevance pup response valosin-containing protein

项目摘要

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.

描述(申请人提供)：我们实验室首次发现VCP突变是遗传性包涵体肌病、骨派杰氏病、额颞痴呆和肌萎缩侧索硬化症的病因，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小鼠的研究已将VCP置于泛素-蛋白酶体信号和自噬途径的交叉点，这两种机制都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。我们开发了第一个带有常见R155H突变的敲入VCP小鼠模型，这种突变具有许多典型的人类疾病的临床特征(1)。与R155H杂合子(VCPR155H/+)小鼠模型的疾病进展不同，纯合子(VCPR155H/R155H)小鼠的肌肉、脑和脊髓病理更严重，大多数存活不超过21天。结构和功能研究表明，纯合子表现出异常的自噬途径和线粒体的增殖。最近的初步研究表明，给怀孕的杂合子母鼠喂食脂肪增加3%的日粮，可以显著提高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，证明增加脂肪饮食可以改善致命的表型。在这一应用中，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。我们还将研究正常饮食和高脂饮食处理的纯合子VCP敲入小鼠中重要的线粒体、自噬和泛素-蛋白酶体分子通路的变化。研究这一观察结果为开发VCP患者及相关疾病的治疗策略提供了机会。