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

• 批准号: 8364893
• 负责人: VIRGINIA Eunice KIMONIS
• 金额: $ 22.23万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 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/8364893
• 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; pup; response; valosin-containing protein

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. PUBLIC HEALTH RELEVANCE: The knock-in homozygous VCP R155H knock-in mouse demonstrates more severe disease compared to the heterozygous R155H VCP mouse model and dies by 21 days. The mice have many of the pathological features typical of hereditary inclusion body myopathy, Paget disease of bone, frontotemporal dementia (IBMPFD) and ALS associated with mutations in the VCP gene. We have recently identified that we can rescue the lethal phenotype by feeding pregnant dams and pups a higher fat diet. This proposal offers the opportunity of utilizing the knock-in homozygous mice for the necessary preclinical studies before evaluating this promising treatment in patients with VCP disease.

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。 公共卫生相关性：与杂合的R155H VCP小鼠模型相比，敲入纯合子VCP R155H小鼠表现出更严重的疾病，并在21天内死亡。这些小鼠具有遗传性包涵体肌病、骨佩吉特病、额颞叶痴呆(IBMPFD)和与VCP基因突变相关的ALS的许多典型病理特征。我们最近发现，我们可以通过给怀孕的母马和幼崽喂食更高脂肪的食物来拯救这种致命的表型。这项建议提供了在评估VCP病患者的这一有希望的治疗之前，利用敲入纯合子小鼠进行必要的临床前研究的机会。