Stem cells and the fibroblast/adipocyte lineage in arrhythmogenic cardiomyopathy

致心律失常性心肌病中的干细胞和成纤维细胞/脂肪细胞谱系

• 批准号: 7825971
• 负责人: Mario Delmar
• 金额: $ 50万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7825971
• 关键词: Adipocytes; Adipose tissue; Adolescent; Adult; Affect; Age; Animal Model; Animals; Applications Grants; Arrhythmia; Arrhythmogenic Right Ventricular Dysplasia; Attention; Behavior; Biological Assay; Biology; Bone Marrow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cells; Cessation of life; Characteristics; Child; Cloning; Code; Communities; Complement; Data; Desmosomes; Development; Disease; Embryo; Epicardium; Epithelial; Epithelial Cells; Experimental Models; Family; Fatty acid glycerol esters; Fibroblasts; Fibroid Tumor; Fibrosis; Functional disorder; Future; Genes; Goals; Grant; Heart; Heart Diseases; Heart Transplantation; Heart failure; Hematopoietic; Hematopoietic stem cells; Human; Hypertrophy; Imagery; Infection; Infiltration; Inflammation; Inherited; Injury; Knock-in Mouse; Knowledge; Lead; Learning; Life; Mechanics; Medical; Mesenchymal; Modeling; Molecular Genetics; Mus; Muscle Cells; Mutant Strains Mice; Mutation; Myocardial; Myocardium; Myofibroblast; Organ; Organism; Pathogenesis; Patients; Phenotype; Play; Population; Procedures; Process; Proliferating; Proteins; Public Health; Radiation Chimera; Rare Diseases; Risk; Role; Running; Source; Staging; Stem cells; Sudden Death; Techniques; Testing; Tissues; United States; Ventricular Arrhythmia; base; blood pump; cell type; disease characteristic; genetic analysis; improved; innovation; migration; minimally invasive; mutant; novel; plakophilin 2; prevent; progenitor; public health relevance; research study; response; stem cell population; young adult

DESCRIPTION (provided by applicant): This grant application is a response to Topic 15-OD (ORDR)-101. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited cardiac disease characterized by severe ventricular arrhythmias, as well as progressive replacement of healthy myocardium with fibrous and fatty tissue leading in many cases to severe heart failure and, in the absence of a heart transplant, death. ARVC has been associated with mutations in desmosomal proteins, most prominently in the gene coding for plakophilin-2 (PKP2). Much attention has been given to the changes that occur in cardiac myocytes following disruption of the desmosome. Yet, myocyte-based experimental models have failed to reproduce the fibrofatty infiltration characteristic of the disease. Here, we shift away from cardiomyocyte-centered hypotheses to propose a new paradigm: that the fibrofatty infiltration has its origins in the behavior of non-myocyte cells. Our focus centers on two stem cell populations capable of generating a cardiac fibroblast lineage: the epithelial cells that comprise the epicardium, and the hematopoietic stem cells. Through the use of novel mouse molecular genetic strategies, and cell biological assays, we will test the hypothesis that loss of desmosomal integrity in these stem cells leads to an increase in the population of fibroblasts and adipocytes in the heart, at the expense of myocardial mass. Specific aims are: 1. To assess the role of PKP2 on migration, proliferation and differentiation of epicardium-derived cells. 2. To generate a murine model of epicardium-specific conditional expression of an ARVC-relevant mutation. 3. To generate and characterize an animal model of hematopoietic stem cell-specific PKP2 deficiency. These studies offer new hypotheses and new experimental models to better understand fibroblast biology in the diseased heart. Moreover, our experiments open the tantalizing possibility that in the future, these stem-cell populations (hematopoietic; epicardial) can be targeted for treatment, to decrease the rate of loss of myocardial mass and prevent the occurrence of heart failure in patients with ARVC. Moreover, although ARVC is, indeed, a "rare disease," cardiac fibrosis is a common occurrence of major medical importance, and control of fibrosis via manipulation of the fibroblast progenitor cells remains largely unexplored. Experimental models generated under the present grant can be instrumental to reduce that particular knowledge gap. Animal models where the stem cell progeny is traceable will become available to the scientific community as a whole. These animals will be utilized on additional experiments where acquired diseases (e.g., LAD occlusion; pacing-induced hypertrophy) are modeled, thus allowing identification of the origin of the resulting fibroblasts. As such, this project is directly relevant to the small community of ARVC-afflicted patients. Yet, as it is often the case with the study of rare diseases, lessons learned from the present project are likely to find applications relevant to the much broader community of patients afflicted with heart disease, the number one killer in the United States. PUBLIC HEALTH RELEVANCE: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a devastating, incurable disease of the heart that can run in families. Patients suffer very severe arrhythmias and are at great risk of sudden death at a young age. As the disease progresses, the heart muscle weakens and becomes replaced with fatty and fibroid tissue, to the point where the heart is unable to pump blood. In the terminal stages (often in young adults), heart transplant becomes the only alternative. Here, we propose that part of the origins of the disease may involve a particular type of stem cells, which may produce excess fatty and fibroid cells. To understand the role of these stem cells in ARVC, and potentially manipulate their function to preserve the heart wall, are the main goals of this grant.

描述（由申请人提供）：本资助申请是对主题15-OD（ORR）-101的回应。致心律失常性右心室心肌病（ARVC）是一种遗传性心脏病，其特征是严重的室性心律失常，以及健康心肌被纤维和脂肪组织进行性替代，在许多情况下导致严重心力衰竭，在没有心脏移植的情况下导致死亡。ARVC与桥粒蛋白的突变有关，最突出的是编码斑嗜蛋白-2（PKP 2）的基因。桥粒破坏后心肌细胞发生的变化引起了人们的广泛关注。然而，基于肌细胞的实验模型未能再现该疾病的纤维脂肪浸润特征。在这里，我们从以心肌细胞为中心的假设转移到提出一个新的范式：纤维脂肪浸润起源于非肌细胞的行为。我们的重点是两个干细胞群能够产生心脏成纤维细胞谱系：上皮细胞，包括心外膜，和造血干细胞。通过使用新的小鼠分子遗传学策略和细胞生物学测定，我们将测试这一假设，即这些干细胞中桥粒完整性的丧失导致心脏中成纤维细胞和脂肪细胞的数量增加，以心肌质量为代价。具体目标是：1。探讨PKP 2在心外膜细胞迁移、增殖和分化中的作用。2.建立ARVC相关突变的心外膜特异性条件表达的小鼠模型。3.建立造血干细胞特异性PKP 2缺陷的动物模型并进行表征。这些研究提供了新的假设和新的实验模型，以更好地了解患病心脏中的成纤维细胞生物学。此外，我们的实验开启了一种诱人的可能性，即在未来，这些干细胞群体（造血细胞;心外膜细胞）可以作为治疗的靶点，以降低ARVC患者心肌质量损失的速率并预防心力衰竭的发生。此外，尽管ARVC确实是一种“罕见疾病”，但心脏纤维化是一种具有重要医学意义的常见疾病，并且通过操纵成纤维细胞祖细胞来控制纤维化在很大程度上仍未被探索。根据目前的赠款产生的实验模型可以有助于缩小这一特定的知识差距。可追踪干细胞后代的动物模型将可供整个科学界使用。这些动物将用于另外的实验，其中获得性疾病（例如，LAD闭塞;起搏诱导的肥大）进行建模，从而允许鉴定所得成纤维细胞的来源。因此，这一项目与受抗逆转录病毒药物影响的小群体直接相关。然而，正如罕见疾病研究的情况一样，从本项目中吸取的经验教训可能会应用于更广泛的心脏病患者社区，心脏病是美国的头号杀手。 公共卫生相关性：致心律失常性右心室心肌病（ARVC）是一种毁灭性的，无法治愈的心脏疾病，可以在家庭中运行。患者患有非常严重的心律失常，并且在年轻时面临猝死的巨大风险。随着疾病的发展，心肌会变弱，并被脂肪和纤维组织取代，直到心脏无法泵血。在晚期（通常是年轻人），心脏移植成为唯一的选择。在这里，我们提出疾病的部分起源可能涉及一种特定类型的干细胞，这可能会产生多余的脂肪和纤维瘤细胞。了解这些干细胞在ARVC中的作用，并潜在地操纵它们的功能以保护心脏壁，是这项资助的主要目标。