Genetic Determinants of Chagas Cardiomyopathy

恰加斯心肌病的遗传决定因素

基本信息

批准号：
9902506
负责人：
CHRISTINE E SEIDMAN
金额：
$ 42.38万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9902506
关键词：
Antibodies Area Arrhythmia Blood Blood Vessels Blood donor CRISPR/Cas technology Candidate Disease Gene Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular system Cell Lineage Cell model Cells Cessation of life Chagas Disease Chronic Clinical Data Collaborations DNA Data Development Dilatation - action Disease Drug resistance Epitopes Etiology Fibroblasts Fibrosis Gene Expression Gene Mutation Genes Genetic Genetic Determinism Genetic Transcription Genotype Goals Heart Heart Diseases Heart Transplantation Heart failure Hispanics Histopathology Human Human Cell Line Human Genetics Hypertension Immigrant Immune Immune response Immunologic Factors Incidence Individual Infection Inflammation Inflammatory Insect Vectors Insecta Knowledge Latin America Latino Lead Methods Migrant Molecular Biology Morphology Mus Muscle Cells Mutagenesis Mutation Myocardial Infarction Neuropathy Newborn Infant Parasites Parasitic infection Pathogenesis Patients Peptides Performance Perinatal Predisposition Pregnant Women Prevalence Proteins Reagent Research Personnel Resistance Risk Sarcomeres Serological Specificity Specimen System Testing Texas Tissues Trypanosoma cruzi Urine Ventricular Whole Blood Woman case control chagasic cardiomyopathy congenital infection effective therapy epidemiology study exome experimental study gastrointestinal genetic variant genome wide association study heart damage heart function heart rhythm in vivo induced pluripotent stem cell inherited cardiomyopathy innovation insight ischemic cardiomyopathy mouse model neglect novel parasite invasion pathogen phospholamban population genetic structure premature prevent rare variant recruit response screening seropositive transcriptome

项目摘要

ABSTRACT Chronic Chagas cardiomyopathy (CCC) is a leading infectious cause of heart failure. CCC emerges in 20- 30% of patients infected with Trypanosoma cruzi, a parasite that is endemic in Latin America. Epidemiologic studies indicate over 7 million Latinos are infected with T. cruzi, including ~300,000 immigrants in the U.S. Infection is transmitted by insect vectors, infected blood donors, and infected pregnant women who transmit the parasite to newborns. CCC emerges after years or decades after quiescent development of progressive ventricular dilatation with diminished systolic performance, conduction system diseases and arrhythmias. CCC is a neglected disease for which there are no effective treatments and due to limited access to cardiac transplantation, most CCC die prematurely. Moreover, the growing burden of T. cruzi infection is predicted to increase the incidence of CCC. This proposal seeks to identify genetic and immune factors that promote CCC and to elucidate how T. cruzi damages the heart. Our studies will capitalize on a collaboration with Dr. A. Pereira and the Brazilian Consortium for Genetics of Chagas Cardiomyopathy, which has amassed clinical data, bio-specimens and explanted CCC hearts from >3,000 subjects. With this extensively revised application we incorporate new Preliminary Results on candidate host and parasite genes that motivate the proposed experiments. Our studies will exploit novel reagents, including a newly constructed and validated capture reagent to sequence T. cruzi exomes from culture, blood and explanted CCC hearts, to identify parasite genetic variants that are enriched in CCC. We propose innovative approaches to assess host immune response in the development of CCC, by comprehensive serologic profiling to identify T. cruzi epitopes that are recognized by host antibodies in patients with and without CCC. We will determine if these antibodies cross react with cardiac proteins. We will also study candidate genes that may promote pathogenesis by perturbing gene expression in iPS cell derived cardiomyocytes and fibroblasts and by in vivo analyses of infected mice. Through parallel studies of fibroblasts and cardiomyocytes we will test if cell-specific responses to T. cruzi contribute to CCC. In addition, we will determine if T. cruzi mutagenesis accounts for resistance to parricidal agents. Together these studies should promote new fundamental knowledge about the mechanisms by which T. cruzi infection perturbs cardiac morphology and function and causes CCC. We aim to: 1) Identify rare genetic variants in humans and parasites that modulate responses to T. cruzi infection and promote CCC; 2) Identify and compare host antibodies in CCC cases and controls to T. cruzi epitopes and cardiac proteins; 3) Compare cardiac transcriptomes in explanted CCC tissues, T. cruzi-infected iPS-CM, genetic and ischemic cardiomyopathies, and unaffected donor hearts; and 4) Analyze cell and mouse models to explore host-pathogen interactions that promote CCC.

抽象的慢性恰加斯心肌病（CCC）是心力衰竭的主要感染原因。 CCC出现在20- 30% 的患者感染克氏锥虫，这是一种在拉丁美洲流行的寄生虫。流行病学研究表明，超过 700 万拉丁美洲人感染了克氏锥虫，其中包括约 30 万美国移民。感染是通过昆虫媒介、受感染的献血者和受感染的孕妇传播的新生儿的寄生虫。 CCC 在进步的静止发展几年或几十年后出现心室扩张伴收缩功能减弱、传导系统疾病和心律失常。 CCC 是一种被忽视的疾病，没有有效的治疗方法，而且由于获得心脏治疗的机会有限移植后，大多数 CCC 过早死亡。此外，预计克氏锥虫感染的负担将日益增加增加 CCC 的发生率。该提案旨在确定促进 CCC 的遗传和免疫因素，并阐明克氏锥虫如何损害心脏。我们的研究将利用与 A. Pereira 博士和巴西人的合作恰加斯心肌病遗传学联盟，收集了临床数据、生物样本和从超过 3,000 名受试者身上移植了 CCC 心脏。通过这个经过广泛修改的应用程序，我们融入了新的激发拟议实验的候选宿主和寄生虫基因的初步结果。我们的研究将利用新型试剂，包括新构建并经过验证的捕获试剂来对 T. cruzi 进行测序来自培养物、血液和移植的 CCC 心脏的外显子组，以鉴定富含 CCC。我们提出了评估 CCC 发展中宿主免疫反应的创新方法，方法是：全面的血清学分析，以确定患者体内宿主抗体识别的克氏锥虫表位有和没有 CCC。我们将确定这些抗体是否与心脏蛋白发生交叉反应。我们也会研究可能通过干扰 iPS 细胞衍生的基因表达来促进发病机制的候选基因心肌细胞和成纤维细胞以及受感染小鼠的体内分析。通过成纤维细胞的平行研究我们将测试对克氏锥虫和心肌细胞的细胞特异性反应是否会导致 CCC。此外，我们将确定克氏锥虫诱变是否是对杀父剂产生抗性的原因。这些研究共同促进了有关 T. cruzi 感染扰乱心脏形态和功能并导致 CCC。我们的目标是： 1) 识别人类和寄生虫中调节对克氏锥虫反应的罕见遗传变异感染并促进CCC； 2) 识别并比较 CCC 病例和对照中的宿主抗体。 cruzi 表位和心脏蛋白； 3) 比较外植 CCC 组织中的心脏转录组，T。 cruzi 感染的 iPS-CM、遗传性和缺血性心肌病以及未受影响的供体心脏；和 4) 分析细胞和小鼠模型，探索促进 CCC 的宿主-病原体相互作用。