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 在田纳西大学，孟菲斯。此应用程序汇集了 多样化和高度有才华的生物医学科学研究小组， 科学合作和研究成就的非凡历史 与SSc有关，其注意力现在集中在 SSc中胶原基质的生物学：1）胶原诱导的 SSc外周血培养物中成纤维细胞样细胞的生长 单核细胞（PBMC），2）基质金属蛋白酶（MMP）-1的难治性 在SSc病变成纤维细胞中，细胞因子上调，和3） 胶原诱导的血小板聚集。项目#1将描述机制 I型胶原（CI）通过其诱导FLC从PBMC向外生长， 胶原蛋白产生的潜在的极其重要的机制 成纤维细胞填充参与SSc纤维发生的组织和器官。 项目#2解决了MMP-1固有抗性的普遍问题 IL-1、TNF α等细胞因子上调病变SSc成纤维细胞， 和bFGF。MMP-1的这种失调可能通过以下方式促进SSc中的纤维化： 导致胶原在其产生的部位的去除减少。 项目#3将克隆并对血小板CI和CIII进行功能研究 受体（R），并将开发阻断肽，可能证明治疗 用于阻止SSc中过度CI和CIII诱导的血小板聚集 患者行政核心和分子资源核心实验室将 支持SCOR的三个项目，提供行政监督， 为每个项目提供必要的支持。SCOR将提供一辆 通过这种方法，可以集中注意高度协同的多学科方法， SSc.合作与协作的精神一直是 多年来，UT-VAMC结缔组织研究小组的成员 再加上田纳西大学孟菲斯分校的承诺， SCOR将确保成功和迅速实现其目标。

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.