The Role of FKBP10 in Recessive Osteogenesis Imperfecta

FKBP10 在隐性成骨不全症中的作用

基本信息

批准号：
8513969
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
项目类别：
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/8513969
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

项目摘要

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.

成骨不全症 (OI) 是脆骨病最常见的遗传形式，其严重程度从轻微表型到严重的早期致死性不等。 OI的主要临床特征是骨脆性和骨量低，而患者还可能出现巩膜发蓝、牙本质发育不全、关节和皮肤松弛、听力障碍和/或颅骨上有虫骨[1]。具体而言，该奖学金重点关注一种基因，该基因的突变会导致隐性 OI 和布鲁克综合征，称为 FK506 结合蛋白 10 (FKBP10)，该基因编码 FKBP65 蛋白 [2, 3]。 FKBP65 蛋白与热休克蛋白 47 (HSP47) 复合，并且它们一起被认为参与内质网中胶原蛋白的陪伴 [4, 5]。目前，我们还不了解 FKBP10 丢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发生改变，特别是由脯氨酰 3-羟化酶-1 (P3H1)、软骨相关蛋白 (CRTAP) 和脯氨酰顺反异构酶亲环蛋白-B 组成的蛋白质复合物改变（PPIB）[6]。有关 Crtap 基因敲除小鼠的初步数据也表明这些小鼠可能存在细胞信号传导缺陷。此外，对 FKPB10 缺失的人类细胞进行的体外研究表明，会出现内质网应激、高尔基体碎片、前胶原聚集以及自噬体数量增加。这表明可能存在强烈的细胞表型，并且未折叠的蛋白质反应途径可能受到影响。我们假设，由于 Fkbp10 丢失导致细胞内条件发生变化，细胞和可能的生化表型的破坏导致由于表型的相似性，不同成骨不全原因之间可能存在共同的机制。我们的目的是通过确定骨骼和结缔组织上 FKBP10 缺失的体内表型、评估 Fkbp10 无效细胞的生化和细胞表型以及评估 Fkbp10 缺失情况下的细胞信号传导缺陷来检验这一假设。这项研究对于建立常见的疾病机制非常重要，这可能为 OI 和布鲁克综合征患者提供潜在的治疗靶点，特别是通过解决可能影响其的细胞信号传导改变和胶原蛋白生物化学改变。国家牙科和颅面研究所是该奖学金的接受机构，因为成骨不全症和布鲁克综合征的特点是颅面表型。