Lead Toxicity in the Skeleton & Its Role in Osteoporosis

描述(由申请人提供)：本计划项目资助申请旨在 明确铅在骨骼中的毒性机制。研究人员有证据表明，这种重金属对骨骼和软骨功能的不利影响导致了骨质疏松等疾病，并阻碍了骨质疏松性骨折的愈合。该计划项目由四个项目组成，其中两个是细胞和分子性质的，一个是基于动物的，一个是临床的。还提出了两个核心，一个是行政核心，一个是组织病理学核心。 项目1：铅对破骨细胞和成骨细胞影响的分子机制；该项目将 研究铅如何影响控制骨吸收和骨形成的关键调控基因。初步数据表明，骨整合蛋白(OPG)、RANK配体和TRIP是相关基因。该项目将包括体外和体内两种成分。项目2：铅对软骨形成和软骨分化的细胞和分子影响；这项研究试图证明软骨形成和软骨的原始调节 差异化；(即BMP的印度刺猬、PTHrP等)铅的影响是复杂的。铅暴露会导致骨骼发育不良，并使受影响的人容易患上骨质疏松症。项目3：铅对骨骼干细胞和骨折愈合的影响；项目3将使用动物模型来证明项目1和2中的发现在活体中表现出来。此外，这项工作还将表征铅阻碍正常骨折愈合的机制。项目4：骨骼铅中毒的临床诊断和治疗方法；该项目将基础科学调查扩展到临床试验。它试图确定骨质疏松症的治疗方法在含铅骨骼和控制血铅水平方面是否有效。该计划项目将定义新的分子途径来解释铅对骨骼和软骨的不利影响。这些途径将在动物身上进行检查和验证，最终结果将转化为临床试验。这项计划项目提供了一个机会，调查铅对骨骼的影响，从“长凳”到“床边”。在这方面，它是独一无二的。

DESCRIPTION (provided by applicant): This Program Project grant application seeks to define the mechanisms of Pb toxicity in the skeleton. The investigators have evidence that the adverse effects of this heavy metal on bone and cartilage function contribute to diseases such as osteoporosis and hinder osteoporotic fracture healing. The Program Project is made up of four projects, two of which are cellular and molecular in nature, one is animal-based and one is clinical. Two cores are also proposed, an Administrative Core and a Histopathology Core. Project 1: Molecular mechanism of lead's effect on osteoclasts and osteoblasts; this project will examine how Pb influences the key regulatory genes controlling bone resorption and bone formation. Preliminary data have implicated osteoprotegrin (OPG), RANK ligand, and TRIP as the genes responsible. The project will have both in vitro and in vivo components. Project 2: Cellular and molecular effects of lead on chondrogenesis and cartilage differentiation; this research seeks to demonstrate that primordial regulators of chondrogenesis and cartilage differentiation; (i.e. the BMP's Indian hedgehog, PTHrP, etc.) are influenced in a complex way by Pb. Lead exposure leads to inappropriate skeletal development and predisposes affected individuals to osteoporosis. Project 3: Lead effects on skeletal stem cells and fracture healing; Project 3 will use an animal model to document that the findings in Project 1 and 2 are manifested in vivo. Additionally, this work will characterize the mechanism of the effect of Pb on hindering normal fracture healing. Project 4: Clinical diagnostic and therapeutic approaches to skeletal lead toxicity; this project extends the basic science investigations into a clinical trial. It seeks to determine if therapeutic approaches for osteoporosis are effective in Pb-containing skeletons and in controlling blood Pb levels. This Program Project will define novel molecular pathways to explain the adverse effects of Pb on bone and cartilage. The pathways will be examined and validated in animals, and ultimately the findings will be translated into clinical trials. This Program Project provides the opportunity to investigate the skeletal effects of Pb from "the bench" to the "bedside". It is unique in this regard.