Systems Biology of Psoriasis

描述(由申请人提供)：本申请涉及广泛的挑战领域(06)使能技术和具体的挑战主题：06-AR-103，皮肤和风湿病的系统生物学。银屑病(PS)是一种复杂的炎症性皮肤病，遗传风险因素和环境触发因素导致皮肤转录组电路的重新布线。到目前为止，人们对牛皮癣的系统生物学的了解受到基因组工具的限制，这些工具既不划算，也不全面。PS影响着多达750万美国人(占总人口的2%-3%)，10%到30%的PS患者会患上牛皮癣关节炎(PSA)。PS和PSA都是严重的疾病，无法治愈，需要复杂的医疗护理和治疗。PS患者的直接和间接医疗保健总成本约为每年112.5亿美元。PS可导致与其他主要疾病一样的残疾，包括糖尿病、心脏病、高血压和抑郁症，并伴有自杀念头。它与克隆氏症、糖尿病、代谢综合征、肥胖症、高血压、心脏病发作、心血管疾病和肝脏疾病等多种并存疾病密切相关。尽管在理解PS改变的细胞通路和遗传风险因素方面取得了进展，但人们仍然知之甚少。目前的治疗方法对患者和他们的医疗保健提供者来说是一个挑战，因为没有一种治疗方法对每个人都有效，一些治疗方法随着时间的推移而失去效果，许多治疗方法与其他治疗方法结合使用，所有的治疗方法都可能导致一系列独特的副作用。随着高通量下一代DNA测序的发展，我们建议识别改变的mRNAs和小的非编码RNA(包括microRNAs)，并模拟这种疾病的改变的网络。这些数据也将是深层序列分析数据的丰富来源，将促进牛皮癣社区的研究。此外，这种疾病网络的改变可能为有针对性的治疗干预铺平道路。这是一项由研究人员提出的合作建议，他们率先对牛皮癣转录组进行了分析，开发了用于分析表达和microRNA序列数据集的工具，并建立了网络。华盛顿大学医学院基因组测序中心的高通量和技术实力，以及大规模并行基因组测序方法的开发，都是实现本提案中描述的工作的技术。我们的多学科协作小组在样品和文库准备方法、下一代测序方法和计算分析方面拥有成熟的专业知识，可以在两年的时间内完成这项提案的目标。牛皮癣是一种无法治愈的皮肤炎症性疾病。它影响着世界各地的许多人，以及2%-3%的美国人。这项研究的预期结果是确定银屑病(PS)中的新网络和细胞因子，这些因素可以作为开发新疗法的靶点。)

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic: 06-AR-103, Systems Biology for Skin and Rheumatic Diseases. Psoriasis (PS) is a complex inflammatory skin disease where genetic risk factors and environmental trigger contribute to the "rewiring" of the circuitry of the transcriptome of the skin. Until now an understanding of its systems biology of psoriasis were limited by genomic tools that were neither cost effective, nor comprehensive. PS affects as many as 7.5 million Americans (2-3% of the population) and between 10 and 30 percent of PS patients develop psoriatic arthritis (PsA). Both PS and PsA are serious conditions for which there are no cures, and warranting sophisticated medical care and therapies. Total direct and indirect health care costs of PS patients are ~ $11.25 billion annually. PS can cause as much disability as other major diseases, including diabetes, heart disease, hypertension and depression accompanied by thoughts of suicide. It goes hand-in-hand with myriad co-morbid conditions such as Crohn's disease, diabetes, metabolic syndrome, obesity, hypertension, heart attack, cardiovascular disease and liver disease. Despite progress in understanding altered cellular pathways and genetic risk factors of PS, it is still poorly understood. Current treatments present a challenge for patients and their health care providers because no one treatment works for everyone, some treatments lose effectiveness over time, many treatments used are in combination with other treatments, and all treatments may cause a unique set of side effects. With the development of high throughput Next-Generation DNA sequencing we are proposing to identify altered mRNAs, and small noncoding RNAs (including microRNAs) and model the altered networks of this disease. These data will also be a rich resource of deep sequence profiling data that will facilitate research by the psoriasis community. Moreover, altered networks of this disease may pave the way for targeted therapeutic intervention. This is a collaborative proposal from investigators who have pioneered the analysis of the psoriasis transcriptome, the development of tools for the analysis of expression and microRNA sequence datasets, and network building. The high throughput, and technological prowess of the genome sequencing center at Washington University school of medicine and the development of methods for massively parallel genome sequencing are technologies enabling the work described in this proposal. Our multidisciplinary collaborative group has proven expertise both in sample and library preparation methods, Next-Generation sequencing methods and computational analysis to complete the aims of this proposal in a two year time-period. Psoriasis is an inflammatory disease of the skin for which there is no cure. It affects many individuals worldwide, and 2-3% of Americans. The expected outcome of this study is the identification of novel networks and cellular factors in psoriasis (PS) that can be targeted for the development of novel treatments. )