Pathogenesis of Novel Forms of Osteogenesis Imperfecta

新型成骨不全症的发病机制

基本信息

批准号：
9974347
负责人：
Brendan Lee
金额：
$ 141.26万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974347
关键词：
2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine Accelerated Phase Address Affect Antibodies Binding Proteins Biochemical Biology Bone Development Bone Diseases COL1A1 gene COL1A2 gene Cell physiology Cells Clinical Collagen Complex Defect Development Diagnostic Diagnostic radiologic examination Estrogen receptor positive FKBP10 gene Fibrillar Collagen Genes Genetic Genetic Diseases Genetic Models Genotype Goals Homeostasis Human Human Genetics Hydroxylation Infrastructure International Knockout Mice Laboratories Ligands Medical center Medicine Minerals Modeling Modification Molecular Molecular Chaperones Mus Mutation Nature Osteoblasts Osteoclasts Osteocytes Osteogenesis Imperfecta Pathogenesis Patients Phase I Clinical Trials Phenotype Physiologic calcification Post-Translational Protein Processing Procollagen Production Program Research Project Grants Proteins Registries Reporting Research Personnel Signal Transduction Signaling Protein Skeletal Development Structural defect Tendon structure Testing Texas Therapeutic Therapeutic Studies Tissues Translating Type I Procollagen Universities WNT1 gene Washington Work base bone bone quality college crosslink diagnostic biomarker functional genomics gene discovery heritable connective tissue disorder human genome sequencing mineralization mouse genetics novel novel marker novel strategies pigment epithelium-derived factor pre-clinical prognostic programs protein complex skeletal dysplasia skeletal tissue trafficking

项目摘要

Overview Project Summary Osteogenesis Imperfecta (OI) is one of the most common heritable disorders of connective tissue. It is characterized by brittle bones, and over the past four decades, the genetics of OI has taught us about the basic mechanisms of procollagen assembly, post-translational modification, secretion, fibril formation and matrix mineralization. In an accelerated phase of discovery over the past 9 years, the identification of new OI genes has further informed us about the determinants of bone quantity and quality during skeletal development and homeostasis. This Program Project Grant (PPG) began in 2010 and has significantly contributed to this rapidly evolving field. In 2006, we reported that mutations in CRTAP caused recessive forms of severe OI (types III and VII). CRTAP is part of a trimeric protein complex including P3H1 and CYB that together are required for prolyl-3-hydroxylation, a poorly understood post-translational modification of clade A fibrillar collagens (e.g., types I, II, and V collagen). We also identified additional type I procollagen binding proteins, FKBP10 and HSP47, as important components in procollagen assembly and trafficking. We and others have since discovered that mutations in the genes encoding these proteins also contribute to the expanding group of brittle bone disorders (BBDs). The overall goal of this PPG is to elucidate the mechanistic consequences of mutations in procollagen and its modification proteins on bone and to translate this into new targeted diagnostic and therapeutic approaches. In this PPG renewal application, we hypothesize that the brittle bone phenotype in OI is a developmental model of abnormal bone quality and quantity that broadly integrates 1) altered matrix-to-cell signaling defects leading to abnormal bone quantity and cellular function, with 2) altered strength, biochemical nature and intermolecular placement of collagen crosslinks leading to abnormal bone mineralization and quality. To test this hypothesis, we will combine mouse genetic modeling, cell based studies, state-of-the-art mass spectrometric analysis of collagen with continued human genetic gene discovery to elucidate basic mechanisms that will inform genotype-based therapy and diagnostic biomarkers. The PPG will leverage infrastructure housed within the Co-Investigators' programs. The PPG is composed of three projects, a Functional Genomics Core, and an Administrative Core. The projects will answer three important questions. Project 1: What are the downstream mechanisms in WNT1 forms of OI and how do mutations affect osteoblast, osteoclast, osteocyte, and matrix function? Project 2: How do mutations in the FKBP65/HSP47 & PLOD2 collagen chaperone complex affect bone development? Project 3: What are the phenotypic and clinical consequences of altered crosslinking in OI patients and mice with defects affecting procollagen modification and trafficking with regard to bone?

概述项目摘要成骨不完美（OI）是结缔组织最常见的可遗传性疾病之一。这是以脆性骨头为特征，在过去的四十年中，Oi的遗传学教会了我们有关 Procollagen组装的基本机制，翻译后修饰，分泌，原纤维形成和基质矿化。在过去9年中发现的加速阶段，识别新OI 基因进一步向我们告知了骨骼发育过程中骨骼数量和质量的决定因素和稳态。该计划项目赠款（PPG）始于2010年，为此做出了重大贡献迅速发展的领域。 2006年，我们报道CRTAP中的突变引起了隐性形式的严重OI （III和VII型）。 CRTAP是三聚合蛋白复合物的一部分，包括P3H1和Cyb在一起脯氨酰3-羟基化所需胶原蛋白（例如I型，II和V胶原蛋白）。我们还确定了其他I型Procollagen结合蛋白， FKBP10和HSP47，作为Procollagen组装和贩运的重要组成部分。我们和其他人有由于发现编码这些蛋白质的基因中的突变也有助于扩张的组脆性骨骼疾病（BBD）。该PPG的总体目标是阐明 Procollagen中的突变及其在骨头上的修饰蛋白，并将其转化为新的目标诊断和治疗方法。在此PPG更新应用中，我们假设脆性骨头 OI中的表型是骨质和数量异常的发展模型，该模型广泛整合1）改变了基质到细胞信号传导缺陷，导致异常骨骼数量和细胞功能，2）改变胶原蛋白交联的强度，生化性质和分子间放置导致异常骨骼矿化和质量。为了检验这一假设，我们将结合小鼠遗传建模，基于细胞的基础研究，胶原蛋白的最新质谱分析，持续人类遗传基因发现阐明将为基于基因型的治疗和诊断生物标志物提供信息的基本机制。 PPG 将利用共同研究人员计划中的基础设施。 PPG由三个组成项目，功能性基因组核心和行政核心。这些项目将回答三个重要的问题。项目1：Wnt1形式的OI的下游机制是什么？突变如何影响成骨细胞，骨细胞，骨细胞和基质功能？项目2：如何突变 FKBP65/HSP47和PLOD2胶原蛋白伴侣复合物会影响骨骼的发育？项目3：什么是 OI患者和小鼠的交联改变的表型和临床后果影响影响关于骨骼的procollagen修改和贩运？

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Coordinated and unique functions of the E-selectin ligand ESL-1 during inflammatory and hematopoietic recruitment in mice.

E-选择素配体 ESL-1 在小鼠炎症和造血募集过程中的协调和独特功能。

DOI：
10.1182/blood-2013-07-514497
发表时间：
2013
期刊：
Blood
影响因子：
20.3
作者：
Sreeramkumar,Vinatha;Leiva,Magdalena;Stadtmann,Anika;Pitaval,Christophe;Ortega-Rodríguez,Inés;Wild,MartinK;Lee,Brendan;Zarbock,Alexander;Hidalgo,Andrés
通讯作者：
Hidalgo,Andrés

A single-stranded telomere binding protein in the nematode Caenorhabditis elegans.

线虫秀丽隐杆线虫中的单链端粒结合蛋白。