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CELLULAR RESPONSES TO INORGANIC PARTICULATES

细胞对无机颗粒的反应

基本信息

批准号：
6607019
负责人：
STEVEN GOLDRING
金额：
$ 48.51万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-22 至 2005-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6607019
关键词：
biomaterial compatibility biomaterial interface interaction cellular immunity clinical research collagenase cytokine dental implants fluorescent dye /probe human subject implant interleukin 1 joint prosthesis lipopolysaccharides medical implant science particle silicates surface property tumor necrosis factor alpha

项目摘要

DESCRIPTION (adapted from the Investigator's abstract): Aseptic loosening of prosthetic implant devices is the major long-term complication after total join replacement (TIR). The local bone destruction (osteolysis) that characterizes this condition can be attributed to the induction of a granulomatous inflammatory reaction at the bone-implant interface. This tissue reaction is initiated and perpetuated by the recruitment and activation of macrophages by prosthetic wear debris. This application will focus on the physical-chemical properties regulating cell responses to particulate orthopedic implant materials, and will explore the potential role of endotoxin contamination in mediating a component of the adverse cell responses. Specific Aim 1 will test the hypothesis that particle surface chemistry and crystal structure are critical determinants of the pattern and magnitude of cell responses. Fluorescent-labeled particles of well characterized, size, shape, surface chemistry and composition will be used to define the influence of specific physical and chemical properties on protein adsorption, the kinetics of particle internalization and cytokine release. These studies will exploit the unique availability of submicron sized UHMWPE particles which exhibit properties similar to authentic retrieved PE wear debris from failed implants. Specific Aim 2 will test the hypothesis that: Lipopolysaccharide (LPS) "contamination" accounts for a component of particle-induced cell responses. These studies will define the differential capacity of particles with different surface chemistry and crystallinity of bind LPS and will assess the effects of particle-associated LPS on cell responses. Specific Aim 3 will test the hypothesis that: the molecular pathways by which particles regulate the IL-1b and TNF- genes differ and that particle-mediated effects involve LPS-dependent and -independent signal transduction systems. These experimental approaches will permit the dissection of the molecular mechanisms and signaling pathways by which foreign particulate materials modulate cell responses. The overall goal of these studies is to increase the understanding of the mechanisms by which particulate wear debris generated from orthopedic (and dental) implants regulate cell responses and to define rigorously the physical and chemical properties that determine the biological activity of the particulate materials. This information could lead to the development of targeted therapeutic interventions for preventing or modulating the adverse cellular and tissue reaction to wear particles. In addition, definition of the specific physical-chemical properties responsible for cell activation could lead to the introduction of materials that generate wear debris with reduced pro-inflammatory properties.

描述(改编自调查者摘要)：无菌松动假体植入装置是全关节置入术后的主要远期并发症更换(TIR)。局部骨质破坏(骨溶解)是其特征这种情况可以归因于肉芽肿的诱发。骨-种植体界面的炎症反应。这种组织反应是由巨噬细胞的募集和激活而启动和持续假肢磨损碎片。本应用将集中在物理化学方面调节细胞对颗粒骨科植入物反应的特性材料，并将探索内毒素污染在调节不良细胞反应的一部分。特定目标1将测试粒子表面化学和晶体结构是细胞反应模式和大小的关键决定因素。具有良好表征、大小、形状、表面的荧光标记颗粒化学和作文将被用来定义特定的影响理化性质对蛋白质吸附、吸附动力学的影响颗粒内化和细胞因子释放。这些研究将利用亚微米级UHMWPE颗粒的独特可用性与从失败的植入物中回收的真实PE磨损碎屑相似的特性。《特定目标2》将检验以下假设：脂多糖(LPS) “污染”是颗粒诱导的细胞反应的一个组成部分。这些研究将定义不同粒子的微分能力结合脂多糖的表面化学和结晶度，并将评估颗粒相关内毒素对细胞反应的影响。《特定目标3》将测试假设：粒子调节IL-1b的分子途径和肿瘤坏死因子基因不同，颗粒介导的效应涉及内毒素依赖和-独立的信号转导系统。这些实验方法将允许对分子机制和信号通路的剖析外来颗粒物通过这种物质来调节细胞反应。整体而言这些研究的目标是通过以下方式增加对机制的理解骨科(和牙科)植入物产生的颗粒磨屑调节细胞反应，严格定义物理和化学决定颗粒材料生物活性的特性。这一信息可能会导致靶向治疗的发展预防或调节不良细胞和组织的干预措施对磨损颗粒的反应。此外，定义了具体的负责细胞激活的物理化学性质可能导致减少磨屑产生的材料介绍具有促炎作用。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel promoter regulates calcitonin receptor gene expression in human osteoclasts.

DOI：
10.1016/j.bbaexp.2007.08.005
发表时间：
2007-11
期刊：
Biochimica et biophysica acta
影响因子：
0
作者：
Zhenxin Shen;T. Crotti;M. Flannery;K. Matsuzaki;S. Goldring;K. Mchugh
通讯作者：
Zhenxin Shen;T. Crotti;M. Flannery;K. Matsuzaki;S. Goldring;K. Mchugh

The role played by cell-substrate interactions in the pathogenesis of osteoclast-mediated peri-implant osteolysis.

细胞基底相互作用在破骨细胞介导的植入术骨溶解的发病机理中所起的作用。

DOI：
10.1186/ar1938
发表时间：
2006
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
Shen Z;Crotti TN;McHugh KP;Matsuzaki K;Gravallese EM;Bierbaum BE;Goldring SR
通讯作者：
Goldring SR

NFATc1 directly induces the human beta3 integrin gene in osteoclast differentiation.