SPARC Modulates Extracellular Matrix Dynamics in Skin

这项研究计划涉及的功能，分泌蛋白的酸性 并富含半胱氨酸）在维持和修复胶原基质中的作用。 皮肤这些目标的动机是基于以下观察： SPARC-null小鼠皮肤的抗张强度低于野生型小鼠 小鼠的尾巴是卷曲的，而无SPARC的动物的尾巴是卷曲的。这两 表型与异常胶原基质一致。此外，最近 他们的实验室数据表明，在糖尿病患者中， 肾细胞和组织。他们假设，细胞分裂素可以调节细胞内的 与富含胶原的基质相互作用。一、皮肤的分子基础 脆弱性和尾部异常将通过测试的功能进行调查， 胶原蛋白1）胶原纤维形成，2）前胶原加工，3）基质 金属蛋白酶调节，和4）胶原凝胶的细胞重排。 第二，探讨了细胞核在调节细胞核活性中的潜在作用。 转氨酶，一种通过形成 共价交联，并通过交联TGF-β来调节TGF-β的活性。 细胞因子的ECM，将得到解决。第三，胶原蛋白的变化 原纤维形成或降解和/或转氨酶活性变化 SPARC-null影响皮肤修复和异物反应的动物模型 将研究与野生型动物的比较。这些研究有可能 有助于理解伤口愈合、生物相容性和 胶原蛋白疾病的发病机制，如Ehlers-Danlos综合征， 加快治疗中新疗法的进展和设计， 解决这些事件。

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.