The Role of PRDM16 in Cardiac Development and Cardiomyopathy

PRDM16 在心脏发育和心肌病中的作用

基本信息

批准号：
10408821
负责人：
Sihem Boudina
金额：
$ 68.64万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408821
关键词：
1p36 Adult Affect Age Alleles Arrhythmia Binding Brown Fat Calcium Cardiac Cardiac Myocytes Cardiac development Cardiomyopathies Cell Death Cell Respiration Cells Cessation of life ChIP-seq Child Chromosome Deletion Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Data Deletion Mutation Deterioration Development Diagnosis Dilated Cardiomyopathy Disease Etiology Fatty Acids Fibrosis Future Gene Deletion Gene Expression Genes Genetic Screening Genetic Transcription Heart Heart Hypertrophy Heart failure Hematopoiesis Human Hypertrophic Cardiomyopathy Individual Knock-in Knock-in Mouse Knockout Mice Lead Left ventricular non-compaction Mediating Metabolic Mitochondria Molecular Morbidity - disease rate Morphology Mus Mutation Myocardial dysfunction Non-compaction cardiomyopathy Nonsense Mutation Nucleotides Oxidative Phosphorylation Pathologic Pathology Pathway interactions Patients Perinatal mortality demographics Phenotype Play Proteins RNA Splicing Regulation Research Role Syndrome Tamoxifen Testing Translational Research Transplantation Variant Work Zinc Fingers arrhythmogenic cardiomyopathy cardiogenesis de novo mutation early onset genomic locus heart function induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes innovation insight mortality mouse model multidisciplinary mutant novel pediatric patients proband programs promoter stem cell function sudden cardiac death therapy development transcription factor transcriptome sequencing treatment strategy young adult

项目摘要

Cardiomyopathies are the major cause of morbidity and mortality in children, with death or transplant occurring in nearly half the patients within the first 2 years of diagnosis. Cardiomyopathies are genetically heterogeneous and mutations in genes encoding sarcomeric, cytoskeletal, mitochondrial, and calcium-handling proteins have been associated with the disease. We identified two pediatric patients with de novo non-sense and splice variant mutations in the transcription factor PR domain 16 (PRDM16) presenting with early onset left ventricular non-compaction (LVNC) that progressed to dilated cardiomyopathy (DCM) in one patient. Furthermore, cardiomyocytes-specific loss of Prdm16 in mice causes LVNC and perinatal lethality while heterozygous mice develop cardiac hypertrophy. Similarly, heterozygous CRISPR knock-in of the non-sense mutation also developed cardiac hypertrophy. To overcome the perinatal lethality in these mice and to characterize the role of PRDM16 in adult cardiac cells, we also generated mice with cardiomyocytes-specific tamoxifen inducible deletion of this gene and show that, similar to the germline heterozygous mice and the Prdm16 knock-in mice, these mice also developed cardiac hypertrophy that progressed into cardiac dysfunction with age. Our preliminary characterization of human induced pluripotent stem cell-derived cardiomyocytes from one proband and cardiomyocytes-specific Prdm16 KO mice reveal a dual role for this transcription factor in gene transcription. Lack of Prdm16 repressed metabolic and oxidative phosphorylation genes whereas it increased fibrotic gene expression. The forgoing scientific premise leads us to hypothesize that PRDM16 plays transcriptional roles pertinent to heart development, metabolic programing and cardiac remodeling and its loss results in LVNC/DCM phenotypes in humans and mice. Our specific aims are: (1) to elucidate the mechanisms underlying cardiomyopathy phenotypes consequent to PRDM16 mutations/deletion in humans and mice and (2) to identify transcriptional mechanisms by which PRDM16 regulates different gene programs in the heart. We have assembled a multidisciplinary team to conduct this highly translational research. This study is novel and highly significant as it shows that PRDM16 is an orchestrator of gene expression in the heart and that its loss in humans and in mice causes LVNC/DCM. Identifying PRDM16 targets and their involvement in cardiomyopathies is key towards a better understanding of the etiology of LVNC/DCM and for the development of therapies for these heterogeneous diseases.

心肌病是儿童发病率和死亡率的主要原因，在诊断的头两年内，近一半的患者发生了死亡或移植。心肌病在遗传上是异质性的，并且在编码肉瘤，细胞骨架，线粒体和钙处理蛋白的基因中与该疾病有关。我们确定了两名在转录因子PR结构域16（PRDM16）中的儿科患者，其中一名患者呈现为扩张的心肌病（DCM）。此外，小鼠中PRDM16的心肌细胞特异性损失会引起LVNC和围产期致死性，而杂合小鼠会发展为心脏肥大。同样，非义突变的杂合CRISPR敲入也会产生心脏肥大。 To overcome the perinatal lethality in these mice and to characterize the role of PRDM16 in adult cardiac cells, we also generated mice with cardiomyocytes-specific tamoxifen inducible deletion of this gene and show that, similar to the germline heterozygous mice and the Prdm16 knock-in mice, these mice also developed cardiac hypertrophy that progressed into cardiac dysfunction with age.我们对人类诱导的多能干细胞衍生的心肌细胞的初步表征，来自一个概率和心肌细胞特异性PRDM16 KO小鼠，揭示了该转录因子在基因转录中的双重作用。缺乏PRDM16抑制代谢和氧化磷酸化基因，而纤维化基因表达增加。放弃的科学前提使我们假设PRDM16在人类和小鼠中扮演与心脏发育，代谢编程和心脏重塑有关的转录角色以及其损失导致LVNC/DCM表型。我们的具体目的是：（1）阐明对人类和小鼠中PRDM16突变/缺失造成的心肌病表型的机制，以及（2）识别PRDM16通过核心调节不同基因程序的转录机制。我们已经组建了一个多学科团队，以进行这项高度转化的研究。这项研究是新颖的，并且非常重要，因为它表明PRDM16是心脏基因表达的编排，并且其在人类和小鼠中的丧失会导致LVNC/DCM。鉴定PRDM16靶标及其参与心肌病是更好地理解LVNC/DCM病因的关键，并为这些异质性疾病的疗法开发。