Precision medicine approaches to chronic inflammatory skin disease of older veterans

由于衰老相关功能障碍，老年人炎症性皮肤病增加 皮肤的变化。考虑到美国人口老龄化和退伍军人人口，这是 提高对老年皮肤病的认识和优化治疗选择势在必行。在……里面 这项建议，我们关注的是老年人的特应性皮炎(AD)，一种未被研究的炎症性疾病 皮肤病亚组疾病负担严重，估计患病率约为5%-11% 在65岁以上的个人中。而老年阿尔茨海默病的明显分子特征是 它似乎包括较少的Th2和增加的Th17炎性细胞 相对于经典的儿童期起病的AD来说，激活。越来越多的炎症性皮肤病 正在接受针对特定炎症途径的治疗(例如，Th2导向的IL-4Rα 特应性皮炎的封锁)；然而，在定义患者水平的疾病方面精度较低 机制是导致治疗失败的原因。约30%的患者对 给予靶向免疫调节药物，可能是因为普遍存在的遗传异质性 这些疾病的潜在原因是免疫过度。中国未得到满足的基本需求 炎症性疾病是精确确定个体分子病理的能力。 病人。慢性炎症性疾病患者水平生物标记物的鉴定 受制于A)与容易检测的DNA相比，表观遗传学(即RNA水平)的作用更大 变异体和B)由于混合免疫和基质的特征而导致的低分子分辨率 细胞。这项建议的目标是1)确定特应性的分子异常 老年人皮炎及其在IL-4Rα阻断治疗中的变化 选择最佳靶向治疗个例的精确医学方法 老年特应性皮炎，一种最终可以扩展到任何慢性皮炎的分子框架 炎症性疾病。我们经验丰富的基因组学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.