Project 2. FKBP10 CHAPERONE COMPLEX AND TRAFFICKING AND ORGANELLE DYSFUNCTION IN

项目 2. FKBP10 伴侣复合体与贩运和细胞器功能障碍

• 批准号: 8508692
• 负责人: Brendan Lee
• 金额: $ 34.89万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8508692
• 关键词: Affect; Autophagocytosis; Autophagosome; Binding; Cartilage; Cells; Collagen Type I; Complex; Contracture; Data; Defect; Deformity; Diagnostic tests; Disease; Extracellular Matrix; Family; Fibroblasts; Fracture; Functional disorder; Genes; Genetic; Genetic Counseling; Goals; Golgi Apparatus; Growth; Homeostasis; Hsp47 protein; Human; Inherited; Instruction; Joints; Knockout Mice; Knowledge; Ligaments; Link; Maintenance; Maps; Mesenchymal; Molecular; Molecular Chaperones; Molecular Target; Mus; Mutation; Organelles; Osteogenesis; Osteogenesis Imperfecta; Outcome; Pain; Pathogenesis; Pathway interactions; Phenotype; Principal Investigator; Process; Proteins; Research; Role; Skeleton; Stress; Tendon structure; Testing; Tissues; Type I Procollagen; Work; base; bone; exome sequencing; improved; in vivo; insight; loss of function mutation; mineralization; novel; programs; skeletal; skeletal disorder; trafficking

Understanding key regulators of normal skeletal function have been facilitated by the study of osteogenesis imperfecta (01) or brittle bone disease. Our genetic studies have shown that humans with loss of function mutations in FKBPIO (which encodes the FKBP65 protein) have progressive deforming 01, which may also be associated with progressive joint contractures. What remains unresolved, but necessary to understand, are the cellular consequences and molecular interactions by which FKBP65 regulates synthesis of type I procollagen and formation of a proper bone extracellular matrix (ECM) leading to normal mineralization. The Specific Aims are: 1. Determine the consequences of FKBP10 loss on cellular phenotype. Loss of FKBP65 has significant effects on cellular phenotype indicating increased ER stress. We will determine the molecular basis for these observations in human 01 cells. 2. Determine the in vivo role of FKBP65 in mesenchymally derived tissues and determine its interaction with other ER-localized proteins. FkbpIO conditional knockout mice have been generated to determine whether the abnormal human cellular phenotype is recapitulated in the mouse. Based on the human phenotype, we will determine tissue-specific roles for Fkbp65 in the FkbpIO null mice.. 3. Determine the molecular basis for other recessive forms of 01. Using autozygosity mapping we have identified three new loci for recessively inherited forms of 01. We hypothesize that, like most genes associated with 01, these genes will be involved in the processing of type I procollagen and that their identification will reveal additional components essential for bone formation. We will use exome sequencing of genes in the autozygous regions to define these new 01 associated genes. The work proposed will determine the role of FKBP10/FKBP65 in mesenchymal tissues and will define new components necessary for normal bone formation. Overall the data generated will determine the molecules necessary for the synthesis, mineralization and maintenance of a normal type I collagen extracellular matrix. RELEVANCE (See instructions): The results of this project will have an immediate impact by providing improved genetic counseling and diagnostic testing for families with brittle bone disease. Determining the mechanism of disease in these new forms of Ol develop will identify disease-based strategies and specific molecular targets for therapy.

了解正常骨骼功能的关键调节剂已通过成骨的研究促进 Imperfecta（01）或脆性骨病。我们的遗传研究表明，功能丧失的人 FKBPIO中的突变（编码FKBP65蛋白）具有渐进变形01，也可能也可能 与渐进式联合签署相关联。尚未解决的内容，但要了解， FKBP65调节I型的合成的细胞后果和分子相互作用是 Procollagen并形成适当的骨外基质（ECM），导致正常矿化。这 具体目的是： 1。确定FKBP10损失对细胞表型的后果。 FKBP65的损失显着 对细胞表型的影响，表明ER应激增加。我们将确定这些分子基础 在人类01细胞中观察。 2。确定FKBP65在间质衍生的组织中的体内作用，并确定其与其与之相互作用 其他ER定位的蛋白质。已经生成了有条件敲除小鼠的FKBPIO 人类细胞表型异常在小鼠中概括。基于人类表型，我们 将确定FKBP65在FKBPIO NULL小鼠中的组织特异性作用。 3。确定其他隐性形式为01的分子基础。使用自动合格映射我们有 确定了三个新的基因座，用于01的隐性遗传形式。我们假设这与大多数基因一样 与01相关，这些基因将参与I型Procollagen的处理，并且它们 识别将揭示出对骨形成必不可少的成分。我们将使用外部测序 自载体区域中的基因定义这些新的01相关基因。 提出的工作将确定FKBP10/FKBP65在间充质组织中的作用，并将定义新的 正常骨形成所需的成分。总体而言，生成的数据将确定分子 正常I型胶原蛋白胶原外基质的合成，矿化和维持所需的所必需。 相关性（请参阅说明）： 该项目的结果将通过提供改进的遗传咨询和 对脆性骨骼疾病的家庭进行诊断测试。确定这些新的疾病机制 OL发展的形式将确定基于疾病的策略和特定的治疗分子靶标。