Precision medicine approaches to chronic inflammatory skin disease of older veterans

由于年龄相关的功能障碍，老年人的炎症性皮肤病增加 皮肤改变考虑到美国人口老龄化和退伍军人人口， 必须提高对老年皮肤病的认识并优化治疗选择。在 在这项建议中，我们关注老年人的特应性皮炎（AD），这是一种研究不足的炎症性皮炎。 具有显著疾病负担的皮肤病亚组，估计患病率约为5-11% 在65岁以上的人群中。虽然老年AD的独特分子特征是 仍然不充分的特点，它似乎包括较少的Th 2和增加的Th 17炎症 相对于典型的儿童期发作的AD的激活。越来越多的炎症性皮肤病 正在接受靶向特定炎症通路的治疗（例如，Th 2导向的IL-4 R α 阻断特应性皮炎）;然而， 机制导致治疗失败。约30%的患者对治疗没有完全反应。 给予靶向免疫调节药物，可能是因为普遍的遗传异质性 这些疾病的根本原因是免疫过度活跃。未满足的基本需求 炎症性疾病是精确确定个体的分子病理学的能力， 患者在慢性炎症性疾病中鉴定患者水平的生物标志物已经被证实是有效的。 A）与容易测定的DNA相比，表观遗传学（即RNA水平）的作用更大 变体和B）由混合的免疫和间质的谱分析导致的差的分子分辨率 细胞该建议的目标是：1）定义特应性过敏的分子异常， 老年人皮炎及其在IL-4 R α阻断治疗后的变化; 2） 精准医学方法，为个体病例选择最佳靶向治疗， 老年特应性皮炎，一个最终可以扩展到任何慢性的分子框架 炎症性疾病。我们的基因组学经验丰富的团队有资格实现这些目标 基于我们发现的单细胞RNA测序衍生的转录特征， 特应性皮炎和寻常型银屑病，以及成功的遗传解剖其他 复杂的皮肤病。

Inflammatory dermatologic disease increases in the elderly due to aging-related dysfunctional cutaneous alterations. Given the aging population of the U.S. and veteran population, it is imperative to improve understanding and optimize treatment choice for elderly skin diseases. In this proposal, we focus on atopic dermatitis (AD) of the elderly, an understudied inflammatory skin disease subgroup with significant disease burden and an estimated prevalence of ~5-11% amongst individuals over 65 years of age. While the distinct molecular features of elderly AD are still undercharacterized, it appears to include lesser Th2 and increased Th17 inflammatory activation relative to classic childhood-onset AD. Increasingly, inflammatory skin disease is being treated with therapies targeting specific inflammatory pathways (e.g. Th2-directed IL-4Rα blockade in atopic dermatitis); however, low precision in defining patient-level disease mechanism contributes to treatment failure. ~30% of patients do not completely respond to a given targeted immunomodulatory drug, likely because of the pervasive genetic heterogeneity underlying these diseases of immunological overactivity. The fundamental unmet need in inflammatory disease is the ability to precisely determine molecular pathology of individual patients. Identification of patient-level biomarkers in chronic inflammatory disease has been hindered by A) a greater role of epigenetics (i.e. RNA levels) compared to easily assayed DNA variants and B) poor molecular resolution resulting from profiling of mixed immune and stromal cells. The goals of this proposal are to 1) define molecular abnormalities underlying atopic dermatitis of the elderly and how they change with IL-4Rα blockade treatment and 2) develop a precision medicine approach for choosing optimal targeted treatment for individual cases of elderly atopic dermatitis, a molecular framework that can eventually be extended to any chronic inflammatory disease. Our genomics-experienced team is qualified to accomplish these goals based on our discovery of single cell RNA-sequencing derived transcriptional signatures in atopic dermatitis and psoriasis vulgaris, as well as successful genetic dissection of other complex skin diseases.