Molecular Mechanisms of Ectopic Bone Formation

描述(申请人提供)：骨质疏松症是一个公共卫生问题 这影响了美国大约2500万人。不管怎样 在病因上，骨质疏松症的特征是骨不平衡。 改建。骨重建涉及到相互作用的协调 成骨细胞和破骨细胞。有关骨形成机制的信息可能 为开发诱导骨的策略提供新的见解 在骨量低的疾病中形成，如骨质疏松。病人 伴Albright遗传性骨营养不良(Aho)和进行性骨病 异型增生(POH)，尽管其他临床特征、形式不同 异位骨。AHO和POH患者也有杂合子生殖系GNASI 编码Gs G蛋白的阿尔法链的基因突变。这些G 蛋白质反过来调节细胞内信号效应器的活动，大多数 其中值得注意的是腺酰环化酶，这种酶合成第二种 信使营地。CAMP影响骨骼发育和/或的机制 重塑尚不完全清楚，但可能涉及基因控制。 表情。临床表现与临床表现明显不同的基础 具有相似GNASI失活突变的患者的不同表型 目前也不清楚。了解GNASI患者的异质性 突变可能会更精确地确定骨骼的机制。 队形。具体地说，提出了以下努力：1)评估基因/表型 异位骨孔患者的相关性。2)确定是否 AHO和POH患者异位骨化的嵌合体分布 反映了在野生型GSCC中获得的体细胞克隆突变 等位基因。3)减少Gs(X)在人骨髓间充质细胞中的表达 这些改变的水平对骨形成的影响。4)分开检查 解释植物体细胞嵌合体的候选基因及其产物 异位骨。5)检查来自骨骼的基因表达的微阵列模式和 AHO和POH患者的其他组织。这一奖项可能会让 获得更多经验和知识的机会，成为 通过增加实验室中受保护的时间，独立调查员。在未来，我想指导其他学生或像我一样的初级教员，并将临床和基础科学培训给科学研究带来的独特、令人兴奋和令人兴奋的视角永垂不朽。

DESCRIPTION (provided by applicant): Osteoporosis is a public health problem that affects approximately 25 million people in the United States. Regardless of the etiology, osteoporosis is characterized by an imbalance in bone remodeling. Bone remodeling involves coordinated interaction between osteoblasts and osteoclasts. Information about mechanisms of bone formation may lead to new insights into the development of strategies to induce bone formation in diseases in which bone mass is low such as osteoporosis. Patients with Albrights Hereditary Osteodystrophy (AHO) and progressive osseous heteroplasia (POH), despite differences in other clinical features, form ectopic bone. Patients with AHO and POH also have heterozygous germline GNASI mutations of the gene encoding the alpha chain of the Gs G protein. These G proteins in turn regulate activity of intracellular signal effectors, most notable of which is adenylyl cyclase, the enzyme that synthesizes the second messenger cAMP. The mechanisms by which cAMP affects bone development and or remodeling are incompletely understood, but likely involve control of gene expression. The basis for the distinct differences in the clinical features and variable phenotypes of patients with similar inactivating GNASI mutations remains unclear as well. Understanding the heterogeneity in patients with GNASI mutations might allow more precise determination of the mechanisms of bone formation. Specifically, efforts are proposed to: 1) Assess genotype/ phenotype correlations in patients with ectopic bone forination. 2) Determine whether the mosaic distribution of ectopic ossification in patients with AHO and POH reflects the acquisition of a somatic clonal mutation, in the wild type Gscc allele. 3) Reduce the expression of Gs(X in human mesenchymal cells and observe the effects on bone formation of these altered levels. 4) Examine separate candidate genes and their products to explain the somatic mosaicism of the ectopic bone. 5) Examine microarray patterns of gene expression from bone and other tissues from patients with AHO and POH. This award might afford the opportunity to gain added experience and knowledge necessary to become an independent investigator by increasing protected time in the laboratory. In the future I would like to mentor other students or junior faculty memjbers like myself and perpetuate the unique and exciting and exciting perspective clinicla and basic science training bring to scientific to scientific investigation.