Cardiac Functional and Structural Implications of Lamin A/C Mutations

Lamin A/C 突变对心脏功能和结构的影响

基本信息

批准号：
9137705
负责人：
Anna Grosberg
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-04 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137705
关键词：
Affect Age of Onset Animal Model Architecture Arrhythmia Biological Assay Biomedical Engineering Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular Models Cell Nucleus Cells Cellular Structures Clinical Complex Cytoskeleton DNA DNA Sequence Alteration Data Defect Dermal Development Diagnosis Diagnostic Disease Disease model Doctor of Philosophy Etiology Family Fibroblasts Frequencies Gene Expression Gene Mutation Genes Genetic Genomics Genotype Goals Health Heart Heart Diseases Heart failure In Vitro Individual Inherited Knowledge Laboratories Lamin Type A Lead Length Mechanics Medical Methods Morbidity - disease rate Morphology Muscle Cells Muscle Weakness Mutation Nuclear Nuclear Envelope Nuclear Lamina Organ Pathogenicity Pathway interactions Patients Phenotype Physiological Play Proteins Research Risk Role Severities Signal Transduction Stress Structure Structure-Activity Relationship Sudden Death Supporting Cell Symptoms Techniques Testing Therapeutic Tissue Engineering Tissues Translational Research Variant cell motility exome sequencing fluorescence imaging genetic information genomic variation heart cell improved induced pluripotent stem cell innovation insight practical application programs response screening self assembly sudden cardiac death trait transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Cardiomyopathies and arrhythmia are conditions with high morbidity and limited therapies. Although a vast number of genes have been discovered to contribute to the etiology of these diseases, translational research- the practical application of genetic knowledge to improve screening, diagnosis, and treatment for affected individuals and their families-has been limited. One major obstacle is the lack of functional studies to understand the relationship between genotype and emergent phenotype at multiple physiological scales (cells to tissues) and to identify factors that cause clinical variability between and within families. The proposed study focuses on three affected families each with different mutation in the Lamin A/C (LMNA) gene. LMNA encodes the main protein of the nuclear lamina, the structural matrix of the nuclear envelope that interacts with both the cell nucleus and cytoskeleton. In this proposal, we will test the hypothesis that LMNA mutations are associated with defects in the structure, organization, and function at multiple length-scales. Between families, the severity of the defects is associated with the type of LMNA mutation; and within families, severity is modified by additional genetic factors. Our long term goals are to develop in vitro disease models directly from patients to understand how proper cell structure, tissue organization, and contractile function are affected by the mutation and genetic modifiers. In Specific Aim 1, we will use exome sequencing and in vitro tissue engineering techniques to evaluate genomic variation and defects in cell and nuclear morphology, intracellular architecture, motility, and tissue self-assembly and architecture in fibroblasts from LMNA patients and controls. In Specific Aim 2, we will derive induced pluripotent stem cells (iPS) from fibroblasts and analyze cell structure and tissue organization of iPS-derived cardiomyocytes from LMNA patients and controls. In Specific Aim 3, we will use RNA sequencing to test for altered gene expression and the "Heart-on-a-Chip" to characterize contractility function (frequency, systolic, diastolic, and twitch stresses) of iPS-derived cardiomyocytes from LMNA patients and controls. These results combined with information of genetic and phenotypic variances will imply pathways and functionalities we will further study. Understanding of the complex relationship between genotype and emergent phenotype and identifying modifying factors will provide insight into the mechanism of heart disease and may assist in the development of new preventative, diagnostic, and therapeutic strategies.

描述（申请人证明）：心肌病和心律不齐是迄今具有发病率和有限的基因疗法的疾病。他们的家族受到限制。在细胞核和细胞骨架上同时，我们将测试LMNA与逆变性缺陷相关的假设，并在多个家庭之间的功能，与家族之间的功能相关。 LMNA突变；在家族中，严重性是通过患者的遗传因素来改变的。使用外显子组测序和体外组织工程来评估细胞和构造，细胞内结构的基因组变异和缺陷，以及在特定AIM 2中的成纤维细胞中的成纤维细胞中的组织自组装和结构。）从成纤维细胞中分析了来自LMNA患者的IPS衍生的YTE的Celyze细胞结构和组织的组织，我们将使用RNA测序来测试改变基因表达的改变和“心chip” （频率，系统，舒张压和抽搐应力）来自LMNA患者的IPS源性ES和对照组的遗传和表型变化的启动，这意味着我们将进一步研究RS。并可能有助于开发新的预防剂和治疗性GIE。