The Role of FKBP10 in Recessive Osteogenesis Imperfecta

FKBP10 在隐性成骨不全症中的作用

• 批准号: 8331763
• 负责人: CARESSA LIETMAN
• 金额: $ 4.3万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8331763
• 关键词: 2-oxoglutarate 3-dioxygenase proline; Accounting; Address; Affect; Autophagosome; Biochemical; Biochemistry; Bone Tissue; COL1A1 gene; COL1A2 gene; Cartilage; Cell physiology; Cells; Characteristics; Chondrocytes; Clinical; Collagen; Collagen Type I; Complex; Connective Tissue; Contracture; Data; Defect; Dentinogenesis Imperfecta; Disease; Endoplasmic Reticulum; Extracellular Matrix; Fellowship; Fibroblasts; Genes; Goals; Golgi Apparatus; Hsp47 protein; Human; Hydroxylation; In Vitro; Inborn Genetic Diseases; Inherited; Joints; Knockout Mice; Lead; Ligaments; Link; Mesenchymal; Modification; Molecular Chaperones; Morphology; Mus; Mutant Strains Mice; Mutation; National Institute of Dental and Craniofacial Research; Null Lymphocytes; Osteoblasts; Osteogenesis Imperfecta; Osteoporosis; Pathogenesis; Pathway interactions; Patients; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Procollagen; Proline; Proteins; Research; Role; Rough endoplasmic reticulum; Sclera; Severities; Signal Transduction; Skeletal system; Skeleton; Skin; Syndrome; Tacrolimus Binding Proteins; Tendon structure; Testing; Tissues; Type I Procollagen; Work; bone; bone mass; cis-trans-Isomerases; craniofacial; cranium; cyclophilin B; endoplasmic reticulum stress; hearing impairment; in vivo; insight; mouse model; new therapeutic target; novel; null mutation; protein complex; response; scoliosis; secretion process; skeletal tissue; therapeutic target; trafficking

Osteogenesis Imperfecta (OI) is the most commonly inherited form of brittle bone disease and displays a spectrum of severity from mild phenotypes to severe early lethality. Key clinical features of OI are bone fragility and low bone mass, whereas patients may also display blue sclera, dentinogenesis imperfecta, joint and skin laxity, hearing impairment and/or wormian bones on the skull [1]. Specifically, this fellowship focuses on a gene in which mutations result in recessive OI as well as Bruck Syndrome termed FK506 Binding Protein 10 (FKBP10) that encodes the FKBP65 protein [2, 3]. The FKBP65 protein complexes with Heat Shock Protein 47 (HSP47) and together they are thought to be involved in chaperoning of collagen in the endoplasmic reticulum [4, 5]. Currently, we do not understand the consequences of FKBP10 loss and its role in collagen and ECM formation. Therefore our goal is to elucidate the role of FKBP10 in the skeleton and how null mutations lead to progressively deforming OI. In other types of recessive OI, the biochemical modifications of collagen are altered, in particular by the complex of proteins consisting of Prolyl-3-Hydroxylase-1 (P3H1), Cartilage Associated Protein (CRTAP) and prolyl cis-trans isomerase cyclophilin-B (PPIB) [6]. Preliminary data concerning the Crtap knockout mice also suggests that there may be cell signaling defects in these mice. In addition, in vitro studies of human cells with FKPB10 loss show ER stress, fragmented Golgi, procollagen aggregates, and increased numbers of autophagosomes. This suggests that there may be strong cellular phenotypes and the unfolded protein response pathway may be affected. We hypothesize that due to changes in intracellular conditions owing to Fkbp10 loss, disruptions in cellular and possibly biochemical phenotypes lead to common mechanisms that may exist between different causes of OI due to the similarity in phenotypes. We aim to test this hypothesis by determining the in vivo phenotypes of FKBP10 loss on skeletal and connective tissues, assessing the biochemical and cellular phenotypes of Fkbp10 null cells, and evaluating cell signaling defects in the absence of Fkbp10. This research is important for establishing common mechanisms of disease which may provide potential therapeutic targets for patients with OI and Bruck syndrome, especially through addressing altered cell signaling and altered collagen biochemistry which may affect it. The National Institute of Dental and Craniofacial Research is the recipient organization of this fellowship because OI and Bruck syndrome are characterized by craniofacial phenotypes.

成骨不完美（OI）是脆性骨骼疾病最常见的形式，它显示出从轻度表型到严重的早期致死性的一系列严重程度。 OI的关键临床特征是骨骼脆弱性和低骨骼质量，而患者也可能显示蓝色硬化症，牙齿发生不完美，关节和皮肤松弛，听力障碍和/或颅骨上的蠕虫骨头[1]。具体而言，该团契的重点是一个基因，其中突变导致隐性OI以及称为FK506结合蛋白10（FKBP10）的布鲁克综合征，该基因编码FKBP65蛋白[2，3]。带有热休克蛋白47（HSP47）的FKBP65蛋白复合物，并被认为它们参与内质网中胶原蛋白的伴侣[4，5]。目前，我们不了解FKBP10损失的后果及其在胶原蛋白和ECM形成中的作用。因此，我们的目标是阐明FKBP10在骨骼中的作用，以及无效突变如何导致OI逐渐变形。在其他类型的隐性OI中，胶原蛋白的生化修饰受到改变，特别是由蛋白质的络合物（由prolyl-3-3-羟化酶1（p3H1）组成的蛋白质复合物），软骨相关蛋白（CRTAP）和prolyl cis-prolyl cis-prolyl cis-trolyl cis-therans-trans-trans-trans-trans-trans-异构酶cymolase cyclilin-b（ppib）[6] [6]。有关CRTAP敲除小鼠的初步数据还表明，这些小鼠可能存在细胞信号传导缺陷。此外，对使用FKPB10损失的人类细胞的体外研究表明，ER应力，高尔基体碎片，Procollagen聚集体和自噬体数量增加。这表明可能存在强烈的细胞表型，并且可能影响展开的蛋白质反应途径。我们假设，由于FKBP10损失，细胞内条件的变化，细胞和可能的生化表型的破坏会导致由于表型的相似性而导致的不同原因之间可能存在的常见机制。我们的目的是通过确定FKBP10在骨骼和结缔组织上损失的体内表型来检验这一假设，评估FKBP10无效细胞的生化和细胞表型，并评估FKBP10缺乏的细胞信号缺陷。这项研究对于建立可能为OI和Bruck综合征患者提供潜在的治疗靶点的疾病的常见机制很重要，尤其是通过解决可能影响其影响的细胞信号和改变的胶原生物化学的改变。国家牙科和颅面研究所是该奖学金的接受组织，因为OI和Bruck综合征的特征是颅面表型。