SCOR on the Pathogenesis of Scleroderma

描述(由申请人提供)： 我们建议建立硬皮病发病机制的SCOR。 在孟菲斯的田纳西大学。此应用程序汇集了一个 多元化、才华横溢的生物医学科学研究人员团队 科学合作和研究成就的非凡历史 与SSC有关，它的注意力现在集中在 1)胶原诱导的自发性硬化症中胶原基质的生物学研究 SSC外周血培养中成纤维细胞样细胞的生长 单个核细胞(PBMC)，2)基质金属蛋白酶-1的不应性 SSC皮损成纤维细胞中细胞因子的上调作用，以及3) 胶原蛋白诱导的血小板聚集。项目1将描述各种机制的特点 I型胶原(CI)通过哪种途径诱导外周血单核细胞向FLC生长 潜在极其重要的机制是胶原蛋白的产生 成纤维细胞存在于参与SSC纤维化形成的组织和器官中。 项目2解决了普遍存在的基质金属蛋白酶-1的固有抵抗力问题 白介素1、肿瘤坏死因子α、肿瘤坏死因子α等细胞因子对皮肤成纤维细胞的上调作用 碱性成纤维细胞生长因子。基质金属蛋白酶-1的这种失调可能通过以下途径导致SSC的纤维化 导致胶原蛋白在其产生部位的去除减少。 项目#3将克隆并对血小板CI和CIII进行功能研究 受体(R)，并将开发出可能在治疗上被证明的封闭肽 可有效阻止CI和CIII过度诱导的SSC中的血小板聚集 病人。一个行政核心和分子资源核心实验室将 支持儿童权利公约的三个项目，提供行政监督和 为每个SCOR项目提供必要的协助。这一SCOR将提供一辆 通过它，可以专注于高度协同的多学科方法 SSC.合作和协作的精神一直是标志 UT-VAMC结缔组织研究组成员多年来 结合田纳西大学孟菲斯分校对此的承诺 SCOR将确保成功和迅速地实现其目标。

DESCRIPTION (provided by applicant): We propose the establishment of a SCOR on the Pathogenesis of Scleroderma (SSc) at the University of Tennessee, Memphis. This application brings together a diverse and highly talented group of biomedical scientific investigators with a remarkable history of scientific collaborations and accomplishments in research related to SSc whose attention has now been focused on selected aspects of the biology of the collagenous matrix in SSc which are 1) collagen-induced outgrowth of fibroblast-like cells from cultures of SSc peripheral blood mononuclear cells (PBMC), 2) refractoriness of matrix metalloproteinase (MMP)-1 in SSc lesional fibroblasts to upregulation by cytokines, and 3) collagen-induced platelet aggregation. Project #1 will characterize mechanisms by which type I collagen (CI) induces the outgrowth of FLC from PBMC, a potentially extremely important mechanism by which collagen-producing fibroblasts populate tissues and organs involved in fibrogenesis of SSc. Project #2 addresses the pervasive problem of an inherent resistance of MMP-1 upregulation in lesional SSc fibroblasts by cytokines such as IL-1, TNFalpha, and bFGF. This dysregulation of MMP-1 likely contributes to fibrosis in SSc by leading to decreased removal of collagen in sites where it is being produced. Project #3 will clone and perform functional studies on platelet CI and CIII receptors (R) and will develop blocking peptides that may prove therapeutically useful in halting excessive CI and CIII induced platelet aggregation in SSc patients. An Administrative Core and Molecular Resources Core Laboratory will support the three projects of the SCOR, providing administrative oversight and necessary assistance to each SCOR project. This SCOR will provide a vehicle through which a highly synergistic multidisciplinary approach can be focused on SSc. The spirit of cooperation and collaboration that has been the hallmark over the years of the members of the UT-VAMC Connective Tissue Research Group combined with the commitment of the University of Tennessee, Memphis to this SCOR will assure a successful and expeditious attaining of its goal.