Lead Toxicity in the Skeleton & Its Role in Osteoporosis

本PO1申请寻求确定骨骼中铅毒性的机制。我们有证据 这种重金属对骨骼和软骨功能的不利影响会导致以下疾病 骨质疏松，阻碍骨质疏松骨折愈合。该计划由四个项目组成，其中两个项目 本质上是细胞和分子的，一个是基于动物的，一个是临床的。还提出了两个核心，一个 行政核心和组织病理学核心。 项目1：铅对破骨细胞和成骨细胞影响的分子机制：本项目将研究 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，骨保护素(OPG)、RANK配体和TRIP是相关基因。该项目 将有体外和体内两种成分。项目2：铅对细胞和分子的影响 软骨形成和软骨分化：本研究试图证明软骨发生和软骨分化的原始调节因子 生长板软骨分化(即骨形态发生蛋白、刺猬、甲状旁腺激素受体等)在 由铅组成的复杂方式。铅暴露会导致不适当的骨骼发育，并易受影响 个人对骨质疏松症的认识。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。另外， 本工作将对铅阻碍正常骨折愈合的作用机制进行研究。项目4： 骨骼铅中毒的临床诊断和治疗方法：该项目扩展了基础科学 对一项临床试验的调查。它试图确定骨质疏松的治疗方法是否 对含铅骨骼和控制血铅水平有效。 该计划项目将定义新的分子途径来解释铅对骨骼的不利影响 和软骨。这些途径将在动物身上进行检查和验证，最终结果将是 转化为临床试验。该项目为研究铅对骨骼的影响提供了机会 从“替补席”到“床边”。在这方面，它是独一无二的。

This PO1 application seeks to define the mechanisms of lead toxicity in the skeleton. We 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 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 lead influences the key regulatory genes controlling bone resorption and bone formation. Preliminary data have implicated osteoprotegerin (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 growth plate cartilage differentiation (i.e. the BMP's, indian hedgehog, PTHrP, etc)are influenced in a complex way by lead. 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 lead's effect 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 lead-containingskeletons and in controllingblood lead levels. This program project will define novel molecular pathways to explain the adverse effects of lead on bone and cartilage. The pathways will be examined and validated in animals and ultimately the findings will be translated into clinical trials. This project provides the opportunity to investigate the skeletal effects of lead from "the bench" to the "bedside". It is uniquein this regard.