Molecular Mechanisms of Ectopic Bone Formation

描述（由申请人提供）：骨质疏松症是一个公共卫生问题 影响了美国大约2500万人无论 在病因学中，骨质疏松症的特征是骨骼失衡， 重塑骨重建涉及以下因素之间的协调相互作用： 成骨细胞和破骨细胞。有关骨形成机制的信息可能 导致新的见解的发展战略，诱导骨 在骨质疏松症等骨量较低的疾病中形成。患者 Albrights遗传性骨营养不良（AHO）和进行性骨 异型增生（POH），尽管在其他临床特征的差异，形式 异位骨患有AHO和POH的患者也具有杂合子生殖系GNASI 编码GsG蛋白α链的基因突变。这些G 蛋白质反过来调节细胞内信号效应物的活性， 其中值得注意的是腺苷酸环化酶，该酶合成第二个 信使cAMP。cAMP影响骨发育和/或 重塑还不完全清楚，但可能涉及基因控制， 表情在临床特征上的明显差异的基础， 具有相似失活GNASI突变的患者的可变表型 也不清楚。了解GNASI患者的异质性 突变可能允许更精确地确定骨的机制， 阵具体而言，建议努力：1）评估基因型/表型 异位骨形成患者的相关性。2)确定是否 AHO和POH患者异位骨化的镶嵌分布 反映了在野生型GSCC中获得体细胞克隆突变， 等位基因3)降低人骨髓间充质细胞中Gs（X）的表达，观察 这些改变的水平对骨形成的影响。4)分别检查 候选基因及其产物来解释体细胞嵌合现象的研究 异位骨5)检查来自骨骼的基因表达的微阵列模式， AHO和POH患者的其他组织。这个奖项可能会让 有机会获得更多的经验和知识，成为一个 通过增加在实验室的受保护时间来保护独立调查员。 在未来，我想指导其他学生或像我这样的初级教师，并使临床和基础科学培训为科学研究带来的独特、令人兴奋和令人兴奋的观点永久化。

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.