Systems biology frameworks to unravel mechanisms driving complex disorders

项目摘要/摘要 这个应用程序提出了一个培训计划，以整合PI，Varadan博士之前在 信息学和机器学习在Barrett病病因和进展研究中的应用 食道，一种具有重大公共卫生意义的胃肠道疾病。瓦拉丹博士以前的大部分 研究涉及开发智能算法和信息学方法来解码 复杂生物系统内的相互联系，仅对临床需求和 翻译研究中涉及的复杂性。拟议的项目将提供广泛和深入的 指导经验侧重于巴雷特食道的临床和生物学方面，以及补充 具有使用临床前模型系统研究生物学机制的知识。总体目标是 扩大PI在设计和开展翻译研究方面的经验和培训，重点是 胃肠道(GI)疾病。这一目标将通过教学和研究相结合的方式实现。 在凯斯韦斯特翻译研究人员的杰出指导团队下开展的活动 储备大学，在胃肠道疾病的临床管理、分子遗传学方面取得的成就 以及与肠道疾病相关的炎症过程。因此，这项提议充分利用了Dr。 Varadan的计算背景，以解决生物医学研究中迫切且未得到满足的需求 社区开发可靠的分析方法，可以量化个人的信令网络活动 通过整合多组学测量来获取生物样本。我们最近构思了一种系统生物学 计算框架Inflo，它集成了分子图谱数据来解码分子的功能状态 支持复杂人类疾病的细胞/分子过程。巴雷特食道就是这样一种复杂的食道 疾病对公共卫生的重要性日益增加，因为它是致命癌症的已知先兆， 食管腺癌。鉴于Barrett病的病因和发病机制 食道仍然难以捉摸，这项提议的一个主要目标是联合使用Inflo框架 来自初级组织队列的分子图谱，体外和体内模型系统，以建立 BE发病和疾病复发的分子路线图，从而阐明统一的机制 是这种疾病的潜在原因。这种系统生物学方法将使以证据为基础的 Barrett‘s食道的诊断/预后生物标志物及高危人群的预防策略 人口。

Project Summary/Abstract This application proposes a training program to integrate the PI, Dr. Varadan's previous research efforts in informatics and machine learning into investigations pertaining to the etiology and progression of Barrett's Esophagus, a gastrointestinal disorder of significant public health interest. Much of Dr. Varadan's previous research has involved developing intelligent algorithms and informatics approaches to decode the interconnections within complex biological systems, with only a basic understanding of the clinical needs and complexities involved in translational research. The proposed project would provide a broad and in-depth mentored experience focused on clinical and biological aspects of Barrett's Esophagus, as well as added knowledge in the use of preclinical model systems to investigate biological mechanisms. The overall goal is to expand the PI's experience and training in the design and conduct of translational studies focused on gastrointestinal (GI) diseases. This objective will be achieved through a combination of didactic and research activities conducted under an exceptional mentoring team of translational researchers at Case Western Reserve University, spanning achievements across clinical management of GI disorders, molecular genetics and inflammatory processes associated with diseases of the gut. Accordingly, this proposal leverages Dr. Varadan's computational background to address an urgent and unmet need within the biomedical research community to develop reliable analytic approaches that can quantify signaling network activities in individual biological samples by integrating multi-omics measurements. We recently conceived a systems biology computational framework, InFlo, which integrates molecular profiling data to decode the functional states of cellular/molecular processes underpinning complex human diseases. Barrett's esophagus is one such complex disease gaining increasing importance to public health, as it is the known precursor to the deadly cancer, esophageal adenocarcinoma. Given that the mechanisms underlying the etiology and pathogenesis of Barrett's Esophagus remain elusive, a major objective of this proposal is to employ the InFlo framework combined molecular profiles derived from primary tissue cohorts, in vitro and in vivo model systems to establish the molecular roadmap of BE pathogenesis and disease recurrence, thus elucidating unifying mechanisms underlying this disease. This systems biology approach would enable the development of evidence-based, diagnostic/prognostic biomarkers for Barrett's esophagus and inform preventive strategies within at-risk populations.