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Genetic Studies of Sarcomere-based Cardiac Diseases

基于肌节的心脏病的遗传学研究

基本信息

批准号：
9397642
负责人：
Xiaolei Xu
金额：
$ 40.71万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9397642
关键词：
Accounting Address Adult Affect Age Alleles BAG3 gene Benign Biological Assay Biophysics C-terminal Cardiac Myocytes Cardiomyopathies Cells Clinical Collection Data Diagnosis Dilated Cardiomyopathy Disease Doxorubicin Embryonic Development Environmental Risk Factor Exhibits Exons Fiber Foundations Future Genes Genetic Genetic Heterogeneity Genetic Identity Genetic study Genome Heart Diseases Heart Function Tests Heterogeneity Human Human Genetics Individual Knowledge Lead Length Modeling Mus Mutagenesis Mutation Myofibrils N-terminal Pathogenesis Pathogenicity Patients Peptides Phenotype Population Protein Isoforms Proteins RNA Splicing Sarcomeres Site Solid Splice-Site Mutation Technology Testing Therapeutic Therapeutic Effect Variant Zebrafish anoctamin 5 base cohort connectin disease phenotype effective therapy forward genetics genetic approach genome editing knockout animal mutant novel outcome forecast response screening segregation targeted treatment therapeutic development therapeutic target titin 1 trait

项目摘要

Dilated cardiomyopathy (DCM) is a disorder with genetic heterogeneity and variable phenotypes. TITIN truncating variants (TTNtvs)- nonsense, frameshift, and essential splice site, has been found to be the most common genetic factor for DCM. However, TTNtvs are also found in reference populations and it remains unclear why pathogenic TTNtvs were mainly found in exons encoding A-band domains, while TTNtvs in other exons such as those affecting the N-terminal Z-disc domain are likely benign. Moreover, patients with the same TTN mutation can exhibit highly variable disease phenotypes, presumably because of different genetic background in personal genomes. To address these two bottlenecks on TTN-based DCM, we leveraged efficient zebrafish genetics. To fill the first knowledge gap on allelic heterogeneity, we utilized genome-editing technology and generated more than 10 ttntvs affecting either Z-disc or A-band exons in zebrafish. To fill the second knowledge gap on variable phenotypes, we established a novel mutagenesis screening-based strategy and successfully identified 4 genetic modifiers for DOX-induced cardiomyopathy. We premise that some of these modifiers and related therapies for DOX-induced cardiomyopathy might also be applicable to TTN-based DCM. We propose to conduct comprehensive genetic studies of these ttntvs and candidate genetic modifiers to elucidate mechanisms and to seek therapeutic strategies for TTNtv-based DCM. In our specific Aim 1, we aim to define phenotypic traits for ttn-based DCM, and to discern toxic peptide, exon usage and cronos hypotheses for allelic heterogeneity of ttn-based DCM. In our specific Aim 2, we will elucidate novel functions of the short ttn-novex3 isoform, and test the hypothesis that N-terminal ttntvs affecting the ttn-novex3 isoform are cardiomyopathy modifiers. In our specific Aim 3, we will determine whether the 4 modifying mutants for DOX-induced cardiomyopathy also exert similar modifying effects on ttn-based DCM, and which gene can be a therapeutic target. Completion of the proposal will establish zebrafish as an efficient vertebrate model that facilitates the prognosis, diagnosis and therapeutic development for cardiomyopathies including TTN-based DCM.

扩张型心肌病(DCM)是一种具有遗传异质性和表型多样性的疾病。 Titin截断变异体(TTNtvs)-无稽之谈、移码和基本剪接位点，已被发现是 DCM最常见的遗传因素。然而，在参考人群中也发现了TTNtv，它目前尚不清楚为什么致病的TTNtv主要发现在编码A-带结构域的外显子中，而其他外显子中的TTNtv可能是良性的，例如那些影响N-末端Z-Disc结构域的外显子。此外，具有相同TTN突变的患者可以表现出高度可变的疾病表型，推测是因为在个人基因组中具有不同的遗传背景。要解决基于TTN的这两个瓶颈 DCM，我们利用了高效的斑马鱼基因。为了填补关于等位基因异质性的第一个知识空白，我们利用基因组编辑技术，产生了10多个影响Z-Disk或A-band的ttntv 斑马鱼的外显子。为了填补关于可变表型的第二个知识空白，我们建立了一个新的基于诱变筛选的DOX诱变策略及其4种遗传修饰剂的成功鉴定心肌病。我们假设这些改良剂和相关疗法中的一些对DOX诱导的心肌病也可能适用于以TTN为基础的扩张型心肌病。我们建议进行全面的对这些ttntv和候选遗传修饰物的遗传学研究以阐明机制并寻求以TTNTV为基础的扩张型心肌病的治疗策略。在我们的具体目标1中，我们的目标是定义基于TTN的DCM，以及识别毒肽、外显子使用和Cronos假设的等位基因异质性基于TTN的DCM。在我们的具体目标2中，我们将阐明短ttn-novex3亚型的新功能，以及验证影响ttn-novex3亚型的N-末端ttntv是心肌病修饰物的假设。在……里面我们的具体目标3，我们将确定DOX诱导的心肌病的4个修饰突变体对以ttn为基础的扩张型心肌病也有类似的修饰作用，哪个基因可以作为治疗的靶点。该提案的完成将使斑马鱼成为一种高效的脊椎动物模型，从而促进心肌病的预后、诊断和治疗进展，包括基于TTN的扩张型心肌病。