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Using formins to build distinct structures in cardiomyocytes

使用福明在心肌细胞中构建独特的结构

基本信息

批准号：
10254307
负责人：
Margot E Quinlan
金额：
$ 38.06万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254307
关键词：
Actins Architecture Binding Sites Biochemical Biological Models Bundling Cardiac Myocytes Cardiomyopathies Cells Complement Cytokinesis Data Development Dilated Cardiomyopathy Discrimination Disease Drosophila genus Elongation Factor Endocytosis FHOD3 gene Family Filament Genetic Polymorphism Growth Health Human Hypertrophic Cardiomyopathy Immunity In Vitro Intercalated disc Knowledge Length Maintenance Mammals Measures Mediating Microfilaments Modeling Muscle Muscle Cells Muscle Development Mutagenesis Neurons Pattern Play Process Property Protein Isoforms Proteins RNA Splicing Role Sarcomeres Site Specificity Stress Fibers Structure Testing Thin Filament Variant Work alpha Actin base beta Actin cell motility cell type design experimental study family structure gamma Actin in vivo insight knock-down mechanotransduction mutant profilin profilin 1 stem cell differentiation stem cells tool

项目摘要

Project Summary/Abstract Every cell has a complement of distinct actin-based structures that play specific roles. These structures help cells maintain integrity and polarity, they drive endocytosis and cytokinesis, and in the cases of motile and muscle cells, they are a major component of the contractile machinery. Actin nucleators, proteins that stimulate formation of new filaments, are essential determinants of actin architecture. Understanding the design principles that distinguish nucleators, such as formins, provides insight into how they build distinct structures. Formins in the Formin HOmology Domain (Fhod)-family play important roles in development, immunity, muscle maintenance, and other processes. Mammals have two Fhod-family formins, Fhod1 and Fhod3. Fhod3 is enriched in muscle cells, including cardiomyocytes, where it is critical for sarcomere development and maintenance. Fhod1 is predominantly expressed in non-muscle cells but is also expressed in muscle cells. In cardiomyocytes, Fhod1 is associated with non-sarcomeric structures, including costameres and intercalated discs, structures important for cellular integrity and mechanotransduction. Therefore, the cardiomyocyte is an ideal cell type in which to study how two closely related formins build distinct structures. Further, both Fhod1 and Fhod3 are implicated in human cardiomyopathies. Polymorphisms in Fhod3 are thought to account for 1-2% of hypertrophic cardiomyopathy cases. In dilated cardiomyopathies, increased expression of Fhod1 and decreased levels of Fhod3 are detected, consistent with the idea that the two formins play distinct roles. Early studies concluded that Fhod-family formins are not actin nucleators, unlike all other formins studied to date. Models were proposed in which barbed end capping and/or filament bundling are important Fhod activities. However, we recently demonstrated that Drosophila Fhod and human Fhod1 are, in fact, potent nucleators. Interestingly, they permit barbed end elongation but do not accelerate the growth rate, in contrast to most formins. Processive elongation is a hallmark of formins and is considered a mechanism by which formins build longer actin filaments than can be made by other nucleators. Both Fhod1 and Fhod3 are associated with small, actin-dense structures, some of which contain actin filaments of specific length, such as stress fibers and sarcomeres. We propose that nucleators designed to create shorter actin filaments are necessary to build these structures. We also discovered that Fhod1 discriminates between actin isoforms, nucleating non-muscle actin but not muscle actin. Thus we have a new perspective from which to study this important class of formins. We will test the hypotheses that strong nucleation, weak elongation, and isoform specificity are all activities necessary for Fhod1 and Fhod3 to build distinct actin-based structures in muscle cells. To do so, we will combine biochemical analysis with functional tests in human cardiomyocytes derived from stem cells. These cells are a powerful model in which to study muscle development, function, and disease. Thus this work can help us understand how Fhods function and are associated with cardiomyopathies.

项目总结/文摘