SPARC Modulates Extracellular Matrix Dynamics in Skin

这项研究方案涉及SPARC(分泌型酸性蛋白)的功能 和富含半胱氨酸)在胶原基质的维护和修复中 皮肤。实现这些目标的动机是基于观察到的 SPARC基因缺失小鼠皮肤抗张强度低于野生型 而SPARC缺失的动物的尾巴有卷曲的尖端。这两个都是 表型与异常的胶原基质一致。此外，最近 来自他们实验室的数据表明，SPARC调节胶原和转化生长因子-β在 肾脏细胞和组织。他们假设SPARC用来调节细胞 与富含胶原蛋白的基质相互作用。第一，皮肤的分子基础 脆性和尾部异常将通过测试功能进行调查 SPARC在1)胶原纤维形成，2)前胶原加工，3)基质中的作用 金属蛋白酶的调控；4)胶原凝胶的细胞重排。 第二，SPARC在调节细胞活性中的潜在作用 转谷氨酰胺酶，一种使细胞外基质稳定的酶，通过形成 共价交联剂通过交联化转化生长因子-β来调节其活性 与细胞外基质有关的细胞因子，将被提及。第三，胶原蛋白的变化 转谷氨酰胺酶活性的纤维形成或降解和/或变化 影响SPARC中皮肤修复和异物反应的动物模型-空 对野生动物的对比将会被调查。这些研究有可能 有助于了解伤口愈合、生物相容性和 胶原紊乱的发病机制，如Ehler-Danlos综合征，可能 加快治疗和治疗的新疗法的进展和设计 这些事件的解决。

This research proposal addresses the function of SPARC (secreted protein acidic and rich in cysteine) in the maintenance and repair of collagenous matrices in the skin. The motivation for these Aims is based on the observations that the skin of SPARC-null mice is lower in tensile strength than that of wild-type mice and that the tails of SPARC-null animals have curly tips. Both of these phenotypes are consistent with aberrant collagen matrices. In addition, recent data from their laboratory indicate that SPARC regulates collagen and TGF-B in renal cells and tissue. They hypothesize that SPARC serves to modulate cellular interaction with collagen-rich matrices. First, the molecular basis of skin fragility and tail abnormalties will be investigated by testing the function of SPARC in 1) collagen fibrillogenesis, 2) procollagen processing, 3) matrix metalloprotease regulation, and 4) cellular rearrangement of collagen gels. Second, the potential function of SPARC in the regulation the activity of transglutaminase, an enzyme that lends stability to the ECM by the formation of covalent crosslinks and modulates the activity of TGF-B by cross-linking the cytokine to the ECM, will be addressed. Third, how alterations in collagen fibril formation or degradation and/or changes in transglutaminase activity affect animal models of skin repair and foreign body response in SPARC-null versus wild-type animals will be investigated. These studies have the potential to contribute to the understanding of wound healing, biocompatibility, and the pathogenesis of collagen disorders such as Ehlers-Danlos Syndrome that could accelerate the progress and design of new therapies in the treatment and resolution of these events.