Mineralization/Anti-Mineralization Networks in the Skin

描述（由申请方提供）：软结缔组织的异常矿化与许多临床疾病有关，对总体发病率和 人类的死亡率。此外，皮肤矿化（皮肤钙质沉着症）在许多获得性炎症性疾病中很常见，包括进行性系统性硬化症、红斑狼疮和皮肌炎。主要影响皮肤的遗传性异位矿化障碍的原型是家族性肿瘤性钙质沉着症（FTC），这是一组表现为 在严重的炎症反应之前，磷酸钙复合物在皮肤和皮下组织中沉积。目前尚不清楚炎症/组织损伤与矿化过程之间的病理机制联系。我们以前已经证明，FTC（NFTC）的正磷酸盐血症变体是由SAMD 9基因突变引起的，SAMD 9基因的表达受炎性细胞因子（包括TNF-α和IFN-α）的调节。我们还表明，SAMD 9负调控EGR 1，这是一种在组织钙化和炎症调节中具有既定作用的转录因子。因此，NFTC，一种单基因疾病，提供了一个独特的机会来研究异位钙化的机制，作为炎症/组织损伤的结果。拟议的研究是创新的，跨学科和跨机构的，重点是SAMD 9是皮肤矿化/抗矿化网络的关键组成部分的中心假设。对这个基因的一个有趣的观察是，虽然它明显存在于人类和大鼠的基因组中，但由于进化过程中的基因组重排，它已从小鼠中删除。因此，我们建议的创新特征之一是通过最近在Jefferson Animal Core Facilities开发和采用的基于锌指核酸酶的技术开发SAMD 9-/-敲除大鼠。我们相信，拟议的研究将提供新的见解，了解炎症和异位矿化之间的联系知之甚少，在一些获得性和遗传性疾病，他们提供了一个新的平台，开发游戏改变治疗这一目前棘手的疾病组。 公共卫生相关性：本研究的重点是软结缔组织，如皮肤，在异常矿化疾病的病理钙化的机制。这项研究的重点是SAMD 9，这是一种已成为皮肤矿化/抗矿化网络的重要组成部分的分子。预计这些研究将提供信息，导致在一些遗传性和获得性疾病的异常矿化的预防。

DESCRIPTION (provided by applicant): Aberrant mineralization of soft connective tissues has been linked to a number of clinical conditions with significant impact on the overall morbidity and mortality in humans. Furthermore, cutaneous mineralization (calcinosis cutis) is common in a number of acquired inflammatory disorders, including progressive systemic sclerosis, lupus erythematosus and dermatomyositis. The prototype of heritable ectopic mineralization disorders affecting primarily the skin is familial tumoral calcinosis (FTC), a group of disorders manifesting with deposition of calcium phosphate complexes in the skin and subcutaneous tissues, preceded by severe inflammatory reactions. The pathomechanistic links between inflammation/tissue injury and the mineralization processes are currently unknown. We have previously demonstrated that the normophosphatemic variant of FTC (NFTC) is caused by mutations in the SAMD9 gene, the expression of which is regulated by inflammatory cytokines, including TNF-¿ and IFN-¿. We have also shown that SAMD9 negatively regulates EGR1, a transcription factor with an established role in the regulation of tissue calcification and inflammation. Thus, NFTC, a monogenic disorder, provides a unique opportunity to study the mechanisms of ectopic calcification as a consequence of inflammation/tissue injury. The proposed studies are innovative, interdisciplinary and interinstitutional focusing on the central hypothesis that SAMD9 is a critical component of the mineralization/anti-mineralization networks in the skin. An intriguing observation of this gene is that while it is clearly present in the huma and rat genome, it has been deleted from the mouse as a result of genomic rearrangement during evolution. Thus, one of the innovative features of our proposal is to develop a SAMD9-/- knockout rat by zinc finger nuclease-based technologies that have recently been developed and adopted at Jefferson Animal Core Facilities. We are convinced that the proposed studies will provide novel insight into the poorly understood link between inflammation and ectopic mineralization in a number of acquired and heritable disorders, and they provide a novel platform to develop game changing treatments for this, currently intractable, group of disorders. PUBLIC HEALTH RELEVANCE: This study focuses on mechanisms of pathological calcification of soft connective tissues, such as the skin, in aberrant mineralization disorders. This study focuses on SAMD9, a molecule that has emerged as a critically important component of the mineralization/anti-mineralization networks in the skin. These studies are expected to provide information leading to prevention of aberrant mineralization in a number of heritable and acquired diseases.