The role of LEM domain proteins in nuclear function

LEM 结构域蛋白在核功能中的作用

• 批准号: 8077216
• 负责人: PAMELA K. GEYER
• 金额: $ 28.4万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8077216
• 关键词: Affect; Age; Amino Acids; Binding; Binding Proteins; Bone Density; Cardiomyopathies; Cell Nucleus; Cells; Chromatin; Chromosome Structures; DNA Crosslinking; Data; Defect; Development; Disease; Drosophila genus; Drosophila inturned protein; Emery-Dreifuss Muscular Dystrophy; Engineering; Environment; Family; Family member; Female; Functional disorder; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Gonadal structure; Homeostasis; Human; Immunohistochemistry; Interphase; Investigation; Lamins; Maintenance; Mesenchymal Stem Cells; Mitosis; Molecular; Molecular Genetics; Morphogenesis; Mutation; Myopathy; Nuclear; Nuclear Envelope; Nuclear Lamina; Ovarian; Ovary; Pathology; Phenotype; Phylogenetic Analysis; Production; Property; Proteins; Regulation; Regulatory Pathway; Role; Signal Transduction; Site; Site-Directed Mutagenesis; Somatic Cell; Stem cells; Structure; Surface; Tertiary Protein Structure; Tissues; Transactivation; Transcriptional Regulation; Variant; Work; abstracting; barrier-to-autointegration factor; human disease; insight; loss of function; mutant; novel; prevent; protein folding; public health relevance; research study; stem cell niche; stem cell population; tool; transcription factor

DESCRIPTION (provided by applicant): Abstract: The nuclear lamina is a protein meshwork underneath the nuclear envelope (NE) that contributes to chromosome organization and gene regulation. One class of lamina proteins shares an ~40 amino acid LEM domain (LEM-D) that binds Barrier-to-Autointegration Factor (BAF), the conserved chromatin bridging protein. Mutations in genes encoding LEM-D proteins cause several human diseases known as laminopathies, including Emery-Dreifuss muscular dystrophy, cardio- myopathies and bone density disorders. These pathologies are tissue-restricted, even though the relevant LEM-D proteins are broadly expressed. Emerging data suggest that laminopathies arise from defects in homeostasis of mesenchymal stem cell populations. Our studies will define the function of LEM-D proteins in Drosophila to elucidate the role of the nuclear lamina in conferring tissue-specific regulation during development. These studies capitalize on our genetic isolation of mutations in three genes encoding LEM-D proteins. Our investigations have shown that the Drosophila LEM-D proteins have unique and overlapping developmental requirements, with evidence of age-enhanced phenotypes and a role in the morphogenesis of a mesenchymal stem cell niche. In this proposal, three aims are proposed. First, we will define requirements for dBAF during development, to understand how this chromatin binding protein contributes to the interphase functions of LEM-D proteins. Second, we will determine how the LEM-D is used to establish tissue- specific functions of this class of lamina proteins. Third, we will establish how LEM-D proteins contribute to critical regulatory pathways involved in the morphogenesis of the germline stem cell niche. Together, these investigations elucidate how BAF and LEM-D proteins work together in the NE to establish distinct nuclear lamina functions required for tissue development. As such, these studies will provide insights into molecular mechanisms of human laminopathies. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The integrity and organization of the nucleus depends upon the function of the nuclear lamina, a protein meshwork that underlies the nuclear envelope. Alterations in nuclear lamina components cause several human diseases that are associated with tissue-restricted pathology, such as Emery-Dreifuss muscular dystrophy, myocardial diseases and bone density disorders, even though nuclear lamina proteins are found in all cells. Using genetic and molecular approaches in Drosophila, we will determine the function of one class of nuclear lamina proteins, the LEM domain proteins to provide insights into mechanisms of human disease of the nuclear lamina.

描述（由申请人提供）： 摘要：核纤层是核膜（NE）下方的蛋白质网络，有助于染色体组织和基因调控。一类核纤层蛋白共享约 40 个氨基酸的 LEM 结构域 (LEM-D)，该结构域结合屏障自动整合因子 (BAF)，即保守的染色质桥蛋白。编码 LEM-D 蛋白的基因突变会导致多种人类疾病，称为核纤层蛋白病，包括 Emery-Dreifuss 肌营养不良症、心肌病和骨密度障碍。尽管相关的 LEM-D 蛋白广泛表达，但这些病理学是组织限制的。新数据表明，核纤层蛋白病是由间充质干细胞群稳态缺陷引起的。我们的研究将定义果蝇中 LEM-D 蛋白的功能，以阐明核纤层在发育过程中赋予组织特异性调节的作用。这些研究利用了我们对编码 LEM-D 蛋白的三个基因的突变进行的基因分离。我们的研究表明，果蝇 LEM-D 蛋白具有独特且重叠的发育需求，有证据表明其表型随年龄增长而增强，并且在间充质干细胞生态位的形态发生中发挥作用。在该提案中，提出了三个目标。首先，我们将定义开发过程中 dBAF 的要求，以了解这种染色质结合蛋白如何促进 LEM-D 蛋白的间期功能。其次，我们将确定如何使用 LEM-D 来建立此类层蛋白的组织特异性功能。第三，我们将确定 LEM-D 蛋白如何促进参与生殖干细胞生态位形态发生的关键调控途径。这些研究共同阐明了 BAF 和 LEM-D 蛋白如何在 NE 中协同作用，建立组织发育所需的独特核纤层功能。因此，这些研究将为人类核纤层蛋白病的分子机制提供见解。 公共卫生相关性： 项目叙述 细胞核的完整性和组织取决于核层的功能，核层是核膜下方的蛋白质网络。尽管所有细胞中都存在核纤层蛋白，但核纤层成分的改变会导致多种与组织限制性病理学相关的人类疾病，例如埃默里-德莱福斯肌营养不良症、心肌疾病和骨密度紊乱。利用果蝇的遗传和分子方法，我们将确定一类核纤层蛋白（LEM 结构域蛋白）的功能，以深入了解人类核纤层疾病的机制。