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：
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
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/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

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. 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（由申请人提供）：我们的实验室是第一个将VCP突变识别为遗传性包容体肌病的原因，Paget的骨骼疾病，额颞痴呆和营养性侧面硬化症，并在识别这些疾病的潜在分子病原体方面取得了进展。对患者的成肌细胞和杂合R155H小鼠的研究已将VCP置于泛素 - 蛋白酶体信号传导和自噬途径的交集，这两种机制都被认为是造成肌肉内蛋白质降解和肌肉和大脑中异常病理的负责。我们开发了带有常见R155H突变的第一个敲入VCP小鼠模型，该模型具有许多人类疾病的许多临床特征（1）。与R155H杂合（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，脑和脊髓病理学，大多数人存活不超过21天。纯合子表现出异常的自噬途径和线粒体增殖，如结构和功能研究所证明。最近的初步研究表明，喂养怀孕的杂合大坝的饮食脂肪增加了3％，从而显着改善了其纯合后代的生存。这些后代的寿命超过21天，并成功断奶，表明脂肪饮食的增加可以缓解致命的表型。在此应用中，我们建议研究进一步挽救致命表型的脂肪含量最佳百分比。我们还将研究用正常饮食与高脂饮食治疗的纯合VCP敲击小鼠中重要的线粒体，自噬和泛素 - 蛋白酶体分子途径。研究这一观察结果为VCP和相关疾病患者制定有希望的治疗策略提供了机会。公共卫生相关性：与杂合R155H VCP小鼠模型相比，与纯合的VCP R155H敲击小鼠相比表现出更严重的疾病，并在21天后死亡。这些小鼠具有许多遗传包容体肌病，骨骼疾病，额颞痴呆（IBMPFD）的病理特征，以及与VCP基因突变有关的ALS。我们最近确定，我们可以通过喂养孕妇的大坝和更高的脂肪饮食来挽救致命的表型。该提案提供了利用纯合小鼠进行必要的临床前研究的机会，然后再评估VCP疾病患者的这种有希望的治疗方法。