MAST CELLS IN AGING AND WERNER SYNDROME

肥大细胞是免疫系统的重要组成部分，尤其是 在结缔组织和皮肤中。沃纳综合征(WS)是一种罕见的 常染色体隐性遗传病及其个体表现 在“正常”衰老中观察到的许多病理现象，包括白内障， 动脉粥样硬化、糖尿病和癌症。WS的基因WRN有一个 部分氨基酸与中央的RecQ解旋酶家族相似 蛋白的一部分，表明WRN蛋白是DNA和/或 RNA解旋酶，它可能参与核酸修复，复制， 重组或转录。氨基和氨基的势函数 WRN蛋白的羧基区是未知的。我们已经向WRN展示了 该基因在正常人真皮中发现的肥大细胞中高表达 皮肤在体内的表达，而不是在 还有很多其他的组织。这一意想不到的发现促使我们考虑 肥大细胞在改善或促进糖尿病的发生中可能发挥的作用 “正常的”系统性衰老的表现以及肥大的作用 细胞在WS表型中起作用。 在这个RO-3方案中，我们希望检验两个假设：1)损失 WS中功能WRN蛋白的缺失导致异常结缔组织 肥大细胞功能；以及，2)结缔组织的生物学 肥大细胞在“正常”的人类衰老过程中会发生改变。 为了验证这些假设，我们将通过形态计量学研究肥大细胞的数量。 通过检测肥大细胞分化的标志物以及 由肥大细胞分泌的分泌化合物。我们将研究WRN 用RNA原位技术进行基因表达。样本将包括皮肤尸检和 来自WS患者、年龄和性别匹配的对照组和 来自三个年龄段的正常、健康的成年人。 我们提议的实验可能会开辟一条新的研究途径 年龄相关性骨质疏松症未来研究的老龄化研究 心血管疾病，肥大细胞也可能在其中发挥作用。

Mast cells are essential components of the immune system, particularly in connective tissues and the skin. Werner Syndrome (WS) is a rare, autosomal recessive disease, and individuals with the disease exhibit many pathologies observed in "normal" aging, including cataracts, atherosclerosis, diabetes, and cancer. The gene for WS, WRN, has a partial amino acid similarity to the RecQ helicase family in the central portion of the protein, suggesting that the WRN protein is a DNA and/or RNA helicase, which may participate in nucleic acid repair, replication, recombination or transcription. Potential functions of the amino- and carboxy-regions of the WRN protein are unknown. We have shown the WRN gene is highly expressed in mast cells found in the dermis of normal skin in vivo, in contrast to its comparatively low expression in multiple other tissues. This unexpected finding has led us to consider the role mast cells may play in ameliorating or contributing to the manifestations of "normal," systemic aging as well as the role the mast cell plays in the WS phenotype. In this RO-3 proposal, we wish to test two hypotheses: 1) that the loss of a functional WRN protein in WS results in aberrant connective tissue mast cell function; and, 2) that the biology of the connective tissue mast cell is altered in "normal" human aging. To test these hypotheses, we will study mast cell numbers by morphometry and by examination of markers for mast cell differentiation as well as the secretory compounds secreted from mast cells. We will study WRN gene expression by RNA in situ. Samples will include skin autopsy and biopsy specimens from WS individuals, age- and sex-matched controls and normal, healthy adult individuals from three age-groups. Our proposed experiments may open a new avenues of investigation in aging research for future studies of age-associated osteoporosis and cardiovascular disease, where the mast cell may also play a role.