Role of PI3 Kinase p110alpha in Osteoclasts

PI3 激酶 p110alpha 在破骨细胞中的作用

• 批准号: 6924581
• 负责人: Jin Jiang
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924581
• 关键词: Adenoviridae; RNA interference; apoptosis; cellular polarity; cytoprotection; cytoskeleton; gene induction /repression; gene therapy; laboratory mouse; osteoclasts; phosphatidylinositol 3 kinase; physiologic bone resorption; protein isoforms; protein localization; terminal nick end labeling

DESCRIPTION (provided by applicant): Dysfunction of osteoclasts leads to pathological bone loss associated with diseases including rheumatoid arthritis, periodontal disease, osteoporosis and metastatic bone tumors. Signal transduction by a group of enzymes called phosphatidylinositol 3-kinases (PI 3-kinases) is known to be crucial for regulating osteoclastic bone resorption. Members of three distinct classes of PI 3-kinase are expressed in osteoclasts. The classes differ in structure, substrate specificity and targeting elements. They are thought to play distinct physiologic roles, although these divisions are not yet clear. To date, few data are available about the precise role of each type of PI 3-kinase in osteoclasts. The central hypothesis of this study is that the PI 3-kinases have non-identical regulatory roles in osteoclasts. An effective antisense to an isoform of a subclass of the class I PI 3-kinase (p110alpha) has been expressed in mature osteoclasts by adeno-associated virus (AAV) based gene transfer techniques. The current proposal has three specific Aims. First, the extent and specificity of the p110alpha knock down will be confirmed. If necessary, additional knockdown approaches will be utilized. Second, the effects of knocking down expression of p110alpha on cytoskeletal organization, cell polarity, osteoclast number and bone resorption will be examined. Finally, the effects of knocking down expression of p110alpha on osteoclast survival and apoptosis will be determined. In summary, by knocking down expression of p110alpha and characterizing the effects using assays for the development, activity and survival of osteoclasts, we should be able to assign specific roles for this enzyme. These studies could lead to the development of new, specific, bone active pharmaceuticals with the potential to improve dental health.

描述（由申请人提供）：破骨细胞功能障碍导致与类风湿性关节炎、牙周病、骨质疏松症和转移性骨肿瘤等疾病相关的病理性骨质流失。已知一组称为磷脂酰肌醇 3-激酶（PI 3-激酶）的酶的信号转导对于调节破骨细胞骨吸收至关重要。三种不同类别的 PI 3-激酶成员在破骨细胞中表达。这些类别在结构、底物特异性和靶向元件方面有所不同。人们认为它们发挥着不同的生理作用，尽管这些划分尚不清楚。迄今为止，关于每种类型 PI 3-激酶在破骨细胞中的精确作用的数据很少。本研究的中心假设是 PI 3-激酶在破骨细胞中具有不同的调节作用。通过基于腺相关病毒 (AAV) 的基因转移技术，已在成熟破骨细胞中表达了针对 I 类 PI 3 激酶亚类 (p110alpha) 亚型的有效反义。当前的提案有三个具体目标。首先，将确认 p110alpha 敲低的程度和特异性。如有必要，将采用额外的击倒方法。其次，将检查敲除p110α表达对细胞骨架组织、细胞极性、破骨细胞数量和骨吸收的影响。最后，将确定敲除 p110α 表达对破骨细胞存活和凋亡的影响。总之，通过敲低 p110alpha 的表达并使用破骨细胞的发育、活性和存活测定来表征其影响，我们应该能够确定该酶的特定作用。这些研究可能会导致新型、特定的骨活性药物的开发，并有可能改善牙齿健康。