The Function of PEDF in Recessive Osteogenesis Imperfecta

PEDF在隐性成骨不全症中的作用

• 批准号: 8500994
• 负责人: Kyu Sang Joeng
• 金额: $ 5.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500994
• 关键词: Angiogenesis Inhibitors; Biological; Blood; Bone Mineralization Regulation Pathway; Calvaria; Chondrocytes; Clinical; Code; Collagen; Collagen Type I; Data; Defect; Exhibits; Extracellular Matrix; Fellowship; Fishes; Gene Expression; Genes; Genetic Models; Goals; Hereditary Disease; Homeostasis; Human; Human Genetics; Inherited; Knockout Mice; Laboratories; Lead; Mediating; Modeling; Molecular; Mus; Mutation; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis Imperfecta; Osteoid; Osteomalacia; Patients; Pattern; Phenotype; Physiologic calcification; Process; Protease Inhibitor; Proteins; Recombinants; Research; Role; Serpins; Severities; Signal Pathway; Signal Transduction; Stream; Testing; Therapeutic; Therapeutic Effect; Transgenic Mice; Virus; angiogenesis; base; bone; bone mass; cell type; effective therapy; gain of function; helper-dependent adenoviral vector; in vivo; loss of function mutation; member; mineralization; mouse model; neuron development; new therapeutic target; novel; null mutation; pigment epithelium-derived factor; skeletal; skeletal tissue; therapeutic development

DESCRIPTION (provided by applicant): Osteogenesis Imperfecta (OI) is the most common 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. This fellowship focuses on a gene, SERPINF1 (serpin peptidase inhibitor, clade F, member 1), in which mutations cause a unique form of OI (type VI). OI type VI is characterized by un- mineralized osteoid and the fish-scale pattern of bone lamellation, which are pathologically distinct from other forms of OI. SERPINF1 encodes pigment epithelium-derived factor (PEDF) which is extensively studied as an anti-angiogenic, neurotrophic, and neuroprotective factor. Although PEDF is expressed in major cell types of skeletal tissue including osteoblasts, osteoclasts, and chondrocytes, its function in bone homeostasis is unknown. Therefore, the goal of this proposal is to elucidate the role of PEDF in bone homeostasis and determine the mechanism by which null mutations of this gene lead to OI type VI. I will also evaluate the therapeutic potential of exogenously delivered PEDF using mouse models. In the preliminary data, PEDF knockout mice show reduced bone volume and increased the expression level of MEPE, a negative regulator of bone mineralization. Based on preliminary data, I hypothesize that loss of PEDF alters intracellular signaling which regulates the function of osteoblasts and osteocytes, thus resulting in abnormal bone mineralization. I will test this hypothesis by investigating the PEDF loss- and gain-of-function mouse models and by evaluating cell signaling defects in the absence of PEDF. This research will not only elucidate a novel regulatory mechanism for bone mineralization, but also establish the pathogenic mechanism of OI type VI, thus providing potential therapeutic strategies for patients with OI type VI.

描述（由申请人提供）：成骨不全症（OI）是最常见的脆骨病，其严重程度从轻度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。该奖学金重点关注基因 SERPINF1（丝氨酸蛋白酶抑制剂肽酶抑制剂，进化枝 F，成员 1），该基因的突变会导致独特形式的 OI（VI 型）。 VI 型成骨不全症的特征是未矿化的类骨质和鱼鳞状的骨片，其病理学上与其他类型的成骨不全症不同。 SERPINF1 编码色素上皮衍生因子 (PEDF)，该因子作为抗血管生成、神经营养和神经保护因子被广泛研究。尽管 PEDF 在骨骼组织的主要细胞类型（包括成骨细胞、破骨细胞和软骨细胞）中表达，但其在骨稳态中的功能尚不清楚。因此，本提案的目标是阐明 PEDF 在骨稳态中的作用，并确定该基因的无效突变导致 VI 型 OI 的机制。我还将使用小鼠模型评估外源性 PEDF 的治疗潜力。在初步数据中，PEDF 基因敲除小鼠的骨体积减少，MEPE（骨矿化负调节因子）的表达水平增加。根据初步数据，我推测 PEDF 的缺失会改变调节成骨细胞和骨细胞功能的细胞内信号传导，从而导致骨矿化异常。我将通过研究 PEDF 功能丧失和功能获得小鼠模型以及评估不存在 PEDF 的情况下的细胞信号传导缺陷来检验这一假设。该研究不仅将阐明骨矿化的新调控机制，还将建立VI型OI的致病机制，从而为VI型OI患者提供潜在的治疗策略。