Project 1. PROLY 3-HYDROXYLASE (P3H) COMPLEX AND MATRIX CELL SIGNALING DEFECTS IN

项目 1. PROLY 3-羟化酶 (P3H) 复合物和基质细胞信号传导缺陷

基本信息

批准号：
8508691
负责人：
Brendan Lee
金额：
$ 32.78万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
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/8508691
关键词：
2-oxoglutarate 3-dioxygenase proline Accounting Affect Binding Binding Sites Biochemical Biological Bone Tissue Candidate Disease Gene Cartilage Cells Clinical Collaborations Collagen Collagen Type I Complex Connective Tissue Counseling Data Defect Deposition Diagnosis Diagnostic Dilatation - action Endoplasmic Reticulum Extracellular Matrix Fibrillar Collagen Functional disorder Gene Mutation Gene-Modified Genes Genetic Genetic Heterogeneity Genomics Hydroxylation Inherited Instruction Lead MAP Kinase Gene Maps Marfan Syndrome Medical Mixed Function Oxygenases Molecular Chaperones Mus Mutation Organelles Osteogenesis Imperfecta Osteoid Pathogenesis Pathway interactions Patients Peptidylprolyl Isomerase Phenotype Point Mutation Post-Translational Protein Processing Principal Investigator Process Procollagen-Proline Dioxygenase Proline Proteins Relative (related person)Research Rough endoplasmic reticulum Series Signal Transduction Signaling Molecule Site Skeleton Social Environment Structure Time Tissues Translating Validation Work base bone bone mass cellular engineering crosslink cyclophilin B exome sequencing extracellular fibrillin fibrillogenesis genetic analysis genome sequencing improved in vivo loss of function mineralization notch protein novel response therapeutic development tool trafficking

2-oxoglutarate 3-dioxygenase proline Accounting Affect Binding Binding Sites Biochemical Biological Bone Tissue Candidate Disease Gene Cartilage Cells Clinical Collaborations Collagen Collagen Type I Complex Connective Tissue Counseling Data Defect Deposition Diagnosis Diagnostic Dilatation - action Endoplasmic Reticulum Extracellular Matrix Fibrillar Collagen Functional disorder Gene Mutation Gene-Modified Genes Genetic Genetic Heterogeneity Genomics Hydroxylation Inherited Instruction Lead MAP Kinase Gene Maps Marfan Syndrome Medical Mixed Function Oxygenases Molecular Chaperones Mus Mutation Organelles Osteogenesis Imperfecta Osteoid Pathogenesis Pathway interactions Patients Peptidylprolyl Isomerase Phenotype Point Mutation Post-Translational Protein Processing Principal Investigator Process Procollagen-Proline Dioxygenase Proline Proteins Relative (related person)Research Rough endoplasmic reticulum Series Signal Transduction Signaling Molecule Site Skeleton Social Environment Structure Time Tissues Translating Validation Work base bone bone mass cellular engineering crosslink cyclophilin B exome sequencing extracellular fibrillin fibrillogenesis genetic analysis genome sequencing improved in vivo loss of function mineralization notch protein novel response therapeutic development tool trafficking

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项目摘要

Osteogenesis Imperfecta (01) or brittle bone disease is the most common primary osteodysplasia of the skeleton. In 2006, our group and collaborators defined the mechanistic basis of a unique post-translational modification of fibrillar collagens, i.e., 3-prolyl-hydroxylation, to involve a trimeric complex composed of Cartilage Associated Protein (CRTAP), Prolyl hydroxylase 1 (P3H1 encoded by LEPRE1), and Cyclophiliin B (CYPB) also known as peptidy-prolyl isomerase B (encoded by PPIB). We and others have since demonstrated that mutations in these genes account for the majority of remaining cases that constitute a recessively inherited class of 01. Biochemically, we know that mutations in these genes can be associated with a panoply of biochemical and cell biological changes: 1) intracellular posttranslational overmodification of collagen, 2) dilatation and disorganization of cellular organelles including the rough endoplasmic reticulum (rER), 3) alteration in secretion and fibrillogenesis, 4) dysregulation of extracellular collagen processing including propeptide cleavage and fibril crosslinking, and 5) altered rates of osteoid deposition and matrix mineralization. Still, we do not know how these alterations contribute to the clinical picture of 01. Importantly, the fact that we cannot easily distinguish the clinical features caused by diverse genetic mutations and biochemical alterations supports the hypothesis that there are underiying common mechanisms of cellular and tissue dysfunction that lead to brittle bone. In this project, we propose to dissect the two biochemical activities of the 3-prolyl hydroxylase complex, i.e., 3-prolyl-hydroxylation of fibrillar collagens vs. chaperone function of collagen, to determine whether alterations in matrix cell signaling may be a common mechanism in the pathogenesis of recessive 01, and to identify novel genetic causes of 01, specifically types V and VI. RELEVANCE (See instructions): By studying how mutations that affect a group of genes that modify collagen function translate into bone fragility in osteogenesis imperfecta, we hope to identify novel therapies and improved diagnostic tools.

成骨（01）或脆性骨骼疾病是最常见的原发性骨浮肿骨骼。 2006年，我们的小组和合作者定义了独特的翻译后的机械基础原纤维胶原蛋白的修饰，即3-羟基羟基化，以涉及三聚体络合物软骨相关蛋白（CRTAP），羟基羟化酶1（由LEPRE1编码）和环醇蛋白B （CYPB）也称为肽性 - 培养基异构酶B（由PPIB编码）。从那以后，我们和其他人证明这些基因中的突变是构成构成的大多数情况的原因在生物化学上，隐性遗传遗传的级别为01。我们知道这些基因中的突变可以与随着生化和细胞生物学变化的全面变化：1）细胞内翻译后过度修饰胶原蛋白，2）细胞细胞器的扩张和混乱，包括粗糙的内质网（RER），3）分泌和原纤维发生的改变，4）细胞外胶原加工失调包括丙肽裂解和原纤维交联，5）骨质沉积和基质的速率改变矿化。尽管如此，我们不知道这些改变如何促进01的临床情况。重要的是，我们无法轻易区分多种遗传引起的临床特征这一事实突变和生化改变支持了以下假设导致骨骼脆性的细胞和组织功能障碍的机制。在这个项目中，我们建议剖析 3-丙酰羟化酶复合物的两种生化活性，即纤维化的3-羟基羟基化胶原蛋白与胶原蛋白的伴侣功能，以确定基质细胞信号的改变是否可能为隐性01发病机理中的一种常见机制，并确定了01的新遗传原因，专门类型V和VI。相关性（请参阅说明）：通过研究如何影响修饰胶原蛋白功能的一组基因的突变转化为骨骼在成骨的脆性中，我们希望鉴定出新的疗法和改进的诊断工具。