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: 8274838
• 负责人: PAMELA K. GEYER
• 金额: $ 28.38万
• 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/8274838
• 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：核薄片是核包膜（NE）下方的蛋白质网状功能，它有助于染色体组织和基因调节。一类椎板蛋白共享约40个氨基酸LEM结构域（LEM-D），该氨基酸LEM结构域（LEM-D）结合了屏障到自动构成因子（BAF），即保守的染色质桥接蛋白。编码LEM-D蛋白的基因中的突变引起了几种称为椎板病的人类疾病，包括Emery-Dreifuss肌肉营养不良，心脏肌病和骨密度疾病。这些病理是组织限制的，即使相关的LEM-D蛋白被广泛表达。新兴的数据表明，层状病毒是由间充质干细胞群体体内平衡的缺陷引起的。我们的研究将定义果蝇中LEM-D蛋白的功能，以阐明核层中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在编码LEM-D蛋白的三个基因中突变的遗传分离。我们的研究表明，果蝇LEM-D蛋白具有独特的和重叠的发育要求，并具有增强年龄增强的表型的证据，并且在间充质干细胞壁che的形态发生中起作用。在此提案中，提出了三个目标。首先，我们将定义开发过程中DBAF的要求，以了解该染色质结合蛋白如何促进LEM-D蛋白的相间功能。其次，我们将确定如何使用LEM-D来建立此类椎板蛋白的组织特异性功能。第三，我们将建立LEM-D蛋白如何促进与种系干细胞壁iche形态发生有关的关键调节途径。这些研究共同阐明了BAF和LEM-D蛋白如何在NE中共同起作用，以建立组织发育所需的独特的核层状功能。因此，这些研究将提供对人层状病毒分子机制的见解。 公共卫生相关性： 项目叙述核的完整性和组织取决于核层的功能，核层是核包膜构成的蛋白质网状功能。核椎板成分的改变会导致几种与组织限制病理学有关的人类疾病，例如emery-dreifuss肌肉营养不良，心肌疾病和骨密度疾病，即使在所有细胞中都发现了核薄饼蛋白。使用果蝇中的遗传和分子方法，我们将确定一类核薄片蛋白的功能，即LEM结构域蛋白，以深入了解核椎板人类疾病的机制。