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: 8457086
• 负责人: MARY Ellen DEES
• 金额: $ 36.17万
• 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 2014-10-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457086
• 关键词: Abnormal Cell; Adult; Affect; Binding; Binding Sites; Birds; CENPF gene; Cardiac; Cardiac Myoblasts; Cardiac Myocytes; Cardiomyopathies; Cell Cycle Regulation; Cell Differentiation process; 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; stem cell therapy; tool

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.

我们对控制细胞分裂和分化的过程感兴趣 在发育中的胚胎中。这些过程取决于胚胎的类型 组织，必须严格调节以确保适当的大小、比例和功能 每个器官。在某些细胞类型中，例如骨骼肌、细胞分裂和 分化是相互排斥的：细胞首先增殖（通过分裂），然后停止并增殖 开始分化为成熟的肌肉细胞。在其他方面，例如心肌， 增殖和分化在有限的时间内同时发生。在成人中 然而，一旦细胞停止增殖，它们的能力就极其有限。 恢复。在心脏损伤的情况下，例如心肌梗塞或 心肌病，这极大地限制了心脏的愈合能力。相比之下，成人 骨骼肌在受伤时很容易愈合。成人组织中的这些差异 是在胚胎生命中设定的。我们已经鉴定出一个蛋白质家族，LEK 蛋白质， 这对于细胞增殖和分化之间的相互作用似乎很重要 胚胎心脏和骨骼肌。当我们阻止小鼠 LEK 蛋白 由于是在发育中的心脏中形成的，因此所得的心脏小且壁薄。这 鉴于我们已经证明 LEK 蛋白在 肌细胞增殖和分化。因此，我们的 LEK 破坏模型将是 研究心脏这些过程的宝贵工具。此外，我们还确定了一个 LEK 蛋白在调节所有细胞生长和分化的关键途径中的作用 细胞，视网膜母细胞瘤蛋白（Rb）途径。 Rb 蛋白最为人所知的是 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与 Rb 蛋白，以及它们如何与另一组已知相互作用的蛋白相关 Rb，E2F 蛋白。我们设计的研究利用了我们的突变 在 LEK 蛋白中产生并在心脏和骨骼肌细胞中表达。和 这些工具，我们可以更好地了解胚胎心脏生长的基本缺陷 与先天性心脏病有关。这可以指导未来的治疗，例如干细胞 疗法，有朝一日从根源上纠正先天性缺陷，甚至刺激 受损的心肌在心肌梗塞等损伤后得以愈合。