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TYPE XII COLLAGEN AND PERIODONTITIS

XII 型胶原蛋白和牙周炎

基本信息

批准号：
2634126
负责人：
NADEEM Y KARIMBUX
金额：
$ 8.4万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-01-01 至 1998-12-31
项目状态：
已结题

项目摘要

The long-term research goal of the proposed project is to understand the pathophysiologic mechanisms of progressive connective tissue breakdown widely experienced in gingivitis and periodontitis. Type XII collagen is a homotrimer made up of alpha1 (XII) chains and found to be present in the periodontal ligament, and in tendons and ligaments, tissues which predominantly contain type I collagen. This molecule belongs to a recently found group of collagens that represent minor constituents of the extracellular matrix and are referred to collectively as FACITs or Fibril Associated Collagens with Interrupted Triple-Helices. The tissue- specific expression of FACITs and the characteristic heterogeneity in their amino-terminal domains strongly suggest that FACITs may play a significant role in organizing the three-dimensional spatial pattern of collagen fibrils in different tissues. As described in Preliminary Studies we have shown that the expression of type XII collagen is significantly associated with the rat PDL and dentogingival fiber regions during the maturing stage. In the healthy periodontium, the dentogingival fibers are arranged in neat, parallel bundles. During the initial stages of inflammation each individual fiber maintains its integrity, but the parallel arrangement is disrupted and the fibers appear dissociated from one another. In this application, we proposed a hypothesis that type XII collagen may be degraded first in gingivitis and periodontitis, leading to collagen fibril disintegration. This molecule may therefore play a significant role in the pathophysiology of progressive periodontal tissue breakdown. As the first step to test our hypothesis, the expression of type XII collagen mRNA will be studied in a well established periodontitis model in the rat. Next, the primary structure of rat XII collagen will be analyzed by molecular cloning and sequencing of rat alpha1 (XII) cDNAs using a primer extension method. The DNA sequence of alpha1(XII) collagen cDNAs will provide deduced peptide sequences based on which several synthetic oligo-peptides will be prepared. The synthetic oligo- peptide will be further used to generate affinity purified polyclonal antibodies against rat type XII collagen. Finally, studies of immunoblotting and immunohistochemistry will be carried out in various stages of gingivitis and periodontitis using the generated anti-rat type XII collagen antibodies. The findings from this project will provide the basis for better understanding of the specific pathophysiologic mechanisms of periodontal disease at the molecular level. Furthermore, both cDNAs and antibodies recognizing rat type XII collagen mRNA/DNA and protein, respectively, can potentially serve as significant tools to investigate the aspects of aging, response to infection, effect of systemic diseases, and genetic disturbances on the periodontium. These studies will serve as an important background for human disease.

拟议项目的长期研究目标是了解进行性结缔组织破坏的病理生理机制对牙龈炎和牙周炎有丰富的经验。 xii型胶原是由α 1（XII）链组成的同源三聚体，在牙周韧带，肌腱和韧带，组织，主要含有I型胶原蛋白。这个分子属于最近发现的一组胶原蛋白，代表了细胞外基质，统称为FACIT或原纤维相关的胶原蛋白与中断的三螺旋。组织- FACIT的特异性表达和FACIT的特征性异质性，它们的氨基末端结构域强烈表明FACIT可能发挥作用，在组织三维空间格局的重要作用，不同组织中的胶原纤维。如初步说明中所述我们的研究表明，XII型胶原的表达是与大鼠牙周膜和牙龈纤维区显著相关在成熟阶段。在健康的牙周组织中，齿龈纤维排列成整齐的平行束。期间在炎症的初始阶段，每根纤维都保持着完整性，但平行排列被破坏，纤维似乎彼此分离。在本申请中，我们提出 XII型胶原可能在牙龈炎中首先降解的假设和牙周炎，导致胶原纤维分解。这因此，这种分子可能在糖尿病的病理生理学中发挥重要作用。进行性牙周组织分解。作为检验我们假设的第一步，将在良好建立的牙周炎模型中研究胶原mRNA 在老鼠。接下来，大鼠XII胶原蛋白的一级结构将是通过大鼠α 1（XII）cDNA的分子克隆和测序分析使用引物延伸方法。 alpha 1（XII）的DNA序列胶原cDNA将提供基于其的推导的肽序列，将制备几种合成的寡肽。合成的寡- 肽将进一步用于产生亲和纯化的多克隆抗体，针对大鼠XII型胶原的抗体。最后，研究免疫印迹和免疫组织化学将在不同的使用生成的防鼠类型的牙龈炎和牙周炎的阶段 XII胶原抗体。该项目的研究结果将为更好地了解牙周炎的具体病理生理机制分子水平上的疾病。此外，cDNA和抗体分别识别大鼠XII型胶原mRNA/DNA和蛋白质，可能作为重要的工具，调查的方面，衰老、对感染的反应、系统性疾病的影响和遗传牙周组织紊乱。这些研究将作为人类疾病的重要背景。