Role of LEK and Rb Protein Interactions in Heart and Skeletal Muscle Development

LEK 和 Rb 蛋白相互作用在心脏和骨骼肌发育中的作用

• 批准号: 7584583
• 负责人: MARY Ellen DEES
• 金额: $ 38.38万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7584583
• 关键词: Abnormal Cell; Adult; Affect; Binding; Binding Sites; Birds; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell division; Cells; Complex; Congenital Abnormality; Critical Pathways; Data; Defect; Development; Differentiation and Growth; Dilated Cardiomyopathy; Embryo; Embryonic Heart; Ensure; Equilibrium; Exhibits; Family member; Future; Goals; Growth; Healed; Heart; Heart Diseases; Human; In Vitro; Injury; Knock-out; Leucine; Life; Light; Mediating; Modeling; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Mutation; Myocardial Infarction; Myocardium; Neonatal; Nuclear; Organ; Pathway interactions; Phase; Process; Proliferating; Property; Protein Binding; Protein Family; Proteins; Retinoblastoma; Retinoblastoma Protein; Role; Set protein; Site; Skeletal Muscle; Skeletal Myoblasts; Skeletal system; Testing; Time; Tissues; Transgenic Animals; Tumor Suppressor Proteins; blastomere structure; cell growth; cell type; congenital heart disorder; design; embryo tissue; embryonic stem cell; healing; in vivo; interest; mouse model; myogenesis; null mutation; prevent; protein expression; protein function; public health relevance; stem cell therapy; tool

DESCRIPTION (provided by applicant): We are interested in the processes which control cell division and differentiation in the developing embryo. These processes are dependent on the type of embryonic tissue, and must be tightly regulated to ensure the proper size, proportion, and function of each organ. In some cell types, such as skeletal muscle, cell division and differentiation are mutually exclusive: cells first proliferate (by dividing), then cease and initiate differentiation into mature muscle cells. In others, such as cardiac muscle, proliferation and differentiation occur together for a finite period of time. In the adult heart, however, once cells stop proliferating they have extremely limited capacity to resume. In the case of cardiac injury, for example in myocardial infarction or cardiomyopathy, this significantly limits the heart's ability to heal. In contrast, adult skeletal muscle heals readily in the case of injury. These differences in the adult tissue are set in embryonic life. We have identified a family of proteins, the LEK proteins, which appear to be important in the interplay between proliferation and differentiation in both embryonic heart and skeletal muscle. When we prevent mouse LEK protein from being made in a developing heart, the resulting heart is small and thin walled. This effect is intriguing in light of the functions we have demonstrated for LEK proteins in muscle cell proliferation and differentiation. Thus, our model of LEK disruption will be a valuable tool in the study of these processes in the heart. Further, we have identified a role of LEK proteins in a pathway critical for regulating growth and differentiation in all cells, the retinoblastoma protein (Rb) pathway. The Rb proteins are best known as tumor suppressors, that is for their role in controlling abnormal cell proliferation, but they also affect differentiation. We propose to further study the relationship between LEK and Rb proteins, and how they relate to another set of proteins well known to interact with Rb, the E2F proteins. The studies we have designed take advantage of mutations we have created in LEK proteins and expressed in heart and in skeletal muscle cells. With these tools, we can better understand fundamental defects of embryonic cardiac growth related to congenital heart disease. This can direct future therapy, such as stem cell therapy, to someday correct congenital defects at their origin and even stimulate damaged cardiac muscle to heal after injury such as myocardial infarction. PUBLIC HEALTH RELEVANCE: We have identified a family of proteins, the LEK proteins, which are important in the interplay between cell proliferation and differentiation during embryonic muscle development. We propose to study how these proteins interact with others known to control muscle development by using a mouse model with disrupted LEK protein expression. Our ultimate goal is to uncover ways to manipulate muscle cell growth and differentiation in the setting of acquired and congenital heart disease.

描述（由申请人提供）：我们感兴趣的是控制发育中的胚胎细胞分裂和分化的过程。这些过程取决于胚胎组织的类型，必须严格调节以确保每个器官的适当大小，比例和功能。在某些细胞类型中，如骨骼肌，细胞分裂和分化是相互排斥的：细胞首先增殖（通过分裂），然后停止并开始分化为成熟的肌肉细胞。在其他组织中，如心肌，增殖和分化在有限的时间内同时发生。然而，在成人心脏中，一旦细胞停止增殖，它们恢复的能力就非常有限。在心脏损伤的情况下，例如在心肌梗塞或心肌病中，这显著限制了心脏的愈合能力。相比之下，成人骨骼肌在受伤的情况下容易愈合。成年组织的这些差异在胚胎期就已经形成了。我们已经确定了一个家族的蛋白质，LEK蛋白，这似乎是重要的胚胎心脏和骨骼肌的增殖和分化之间的相互作用。当我们阻止小鼠LEK蛋白在发育中的心脏中产生时，产生的心脏很小，壁很薄。鉴于我们已经证明了LEK蛋白在肌肉细胞增殖和分化中的功能，这种作用是有趣的。因此，我们的模型LEK中断将是一个有价值的工具，在研究这些过程中的心脏。此外，我们已经确定了LEK蛋白在调节所有细胞生长和分化的关键途径中的作用，即视网膜母细胞瘤蛋白（Rb）途径。Rb蛋白最为人所知的是作为肿瘤抑制因子，即它们在控制异常细胞增殖中的作用，但它们也影响分化。我们建议进一步研究LEK和Rb蛋白之间的关系，以及它们如何与另一组已知与Rb相互作用的蛋白质E2F蛋白相关。我们设计的研究利用了我们在LEK蛋白中创造的突变，并在心脏和骨骼肌细胞中表达。有了这些工具，我们可以更好地了解与先天性心脏病相关的胚胎心脏生长的基本缺陷。这可以指导未来的治疗，如干细胞治疗，有一天纠正先天性缺陷，甚至刺激受损的心肌在心肌梗死等损伤后愈合。公共卫生关系：我们已经确定了一个蛋白质家族，LEK蛋白，这是重要的胚胎肌肉发育过程中细胞增殖和分化之间的相互作用。我们建议研究这些蛋白质如何与其他已知控制肌肉发育的蛋白质相互作用，通过使用LEK蛋白表达中断的小鼠模型。我们的最终目标是发现在获得性和先天性心脏病的背景下操纵肌细胞生长和分化的方法。