Mineralization/Anti-Mineralization Networks in the Skin

描述(申请人提供)：软结缔组织的异常矿化与许多临床情况有关，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疾病的原型是家族性肿瘤钙质沉着症(FTC)，这是一组表现为 伴随着皮肤和皮下组织中磷酸钙复合体的沉积，在此之前会出现严重的炎症反应。炎症/组织损伤和矿化过程之间的病理机制联系目前尚不清楚。我们先前已经证明，正常磷血症性FTC(NFTC)是由SAMD9基因突变引起的，SAMD9基因的表达受到炎性细胞因子的调节，包括肿瘤坏死因子和干扰素。我们还发现SAMD9负性调节Egr1，Egr1是一种转录因子，在组织钙化和炎症的调节中具有既定的作用。因此，NFTC是一种单基因疾病，为研究炎症/组织损伤导致的异位钙化机制提供了独特的机会。拟议的研究是创新的、跨学科的和机构间的，侧重于SAMD9是皮肤矿化/反矿化网络的关键组成部分这一中心假设。对这个基因的一个有趣的观察是，虽然它清楚地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，它已经从小鼠中删除。因此，我们提案的创新特征之一是开发基于锌指核酸酶的SAMD9/-基因敲除大鼠，该技术最近已在杰斐逊动物核心设施开发和采用。我们相信，拟议的研究将为一些获得性和遗传性疾病中炎症和异位矿化之间鲜为人知的联系提供新的见解，并为开发这一目前难以治愈的疾病的游戏规则改变治疗方法提供一个新的平台。 公共卫生相关性：这项研究集中在异常矿化障碍中软性结缔组织(如皮肤)的病理性钙化机制。这项研究的重点是SAMD9，一种已经成为皮肤矿化/反矿化网络中至关重要的组成部分的分子。这些研究有望为预防一些遗传性和获得性疾病的异常矿化提供信息。

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.