Precision Medicine in Inflammatory Bowel Disease: Refining the Clinical and Genomic Predictors of Response to Anti-IL-12/23 Therapy

炎症性肠病的精准医学：完善抗 IL-12/23 治疗反应的临床和基因组预测因子

• 批准号: 10662031
• 负责人: Kelly Colleen Cushing-Damm
• 金额: $ 16.81万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-17 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662031
• 关键词: Abdominal Infection; Affect; American; Attention; Autoimmune; Behavior; Biological; Cells; Chronic; Clinical; Clinical Data; Clinical Trials; Crohn' s disease; Data; Decision Trees; Digestive System Disorders; Disease; Disease Progression; Drug Targeting; Exposure to; Funding; Gastrointestinal Diseases; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Transcription; Genotype; Goals; Health; Health Care Costs; Heterogeneity; Immune; Inflammatory; Inflammatory Bowel Diseases; Institution; Interleukin-12; Intestinal Diseases; Intestinal Obstruction; Intra-abdominal; Investigation; Lead; Learning; Location; Machine Learning; Malignant Neoplasms; Mediating; Metadata; Molecular; Morbidity - disease rate; Natural Immunity; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Selection; Patients; Pattern; Performance; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Price; Psoriasis; Research; Risk; Selection for Treatments; Severities; Signal Transduction; TNF gene; Testing; Therapeutic; Tissues; Training; Trees; Variant; adaptive immunity; biomarker identification; career development; cell type; chronic inflammatory disease; clinical heterogeneity; clinical predictors; cohort; cost; disorder control; evidence base; genetic variant; genome wide association study; genome-wide; genomic data; genomic predictors; improved; insight; interest; novel; personalized care; precision medicine; predicting response; prognostic; programs; response; response biomarker; risk variant; skin disorder; statistics; therapy outcome; tool; transcriptome; transcriptomics; treatment response; Abdominal Infection; Affect; American; Attention; Autoimmune; Behavior; Biological; Cells; Chronic; Clinical; Clinical Data; Clinical Trials; Crohn' s disease; Data; Decision Trees; Digestive System Disorders; Disease; Disease Progression; Drug Targeting; Exposure to; Funding; Gastrointestinal Diseases; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Markers; Genetic Risk; Genetic Transcription; Genotype; Goals; Health; Health Care Costs; Heterogeneity; Immune; Inflammatory; Inflammatory Bowel Diseases; Institution; Interleukin-12; Intestinal Diseases; Intestinal Obstruction; Intra-abdominal; Investigation; Lead; Learning; Location; Machine Learning; Malignant Neoplasms; Mediating; Metadata; Molecular; Morbidity - disease rate; Natural Immunity; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Selection; Patients; Pattern; Performance; Pharmaceutical Preparations; Positioning Attribute; Predisposition; Price; Psoriasis; Research; Risk; Selection for Treatments; Severities; Signal Transduction; TNF gene; Testing; Therapeutic; Tissues; Training; Trees; Variant; adaptive immunity; biomarker identification; career development; cell type; chronic inflammatory disease; clinical heterogeneity; clinical predictors; cohort; cost; disorder control; evidence base; genetic variant; genome wide association study; genome-wide; genomic data; genomic predictors; improved; insight; interest; novel; personalized care; precision medicine; predicting response; prognostic; programs; response; response biomarker; risk variant; skin disorder; statistics; therapy outcome; tool; transcriptome; transcriptomics; treatment response

ABSTRACT Crohn’s disease (CD) is a chronic immune-mediated gastrointestinal disease characterized by significant clinical and molecular heterogeneity. The clinical heterogeneity is evidenced by the wide variation in disease location, severity, and behavior. The molecular heterogeneity is evidenced by the numerous genetic risk loci which have been identified to date. Fortunately, there are an increasing number of therapeutic options for the treatment of CD including blockade of tumor necrosis factor  and blockade of IL-12/23 signaling. Unfortunately, patients rapidly cycle through medications, often due to lack of response, further increasing morbidity and healthcare costs. Therefore, there is an urgent need for data matching the mechanism of the disease to the treatment target to guide treatment selection. Our long-term goal is to improve first-line therapy selection in CD as more therapies become available at biosimilar prices. In this career development proposal, I will focus on acquiring data which provides a deeper understanding of the clinical and molecular attributes which associate with response to anti-IL-12/23 therapy to improve drug positioning and first-line therapy selection for this class of therapy in CD. We have shown that CD patients with autoimmune skin disease preferentially respond to anti-IL-12/23 therapy. We will utilize machine learning to identify additional clinical patterns which associate with preferential response to therapy, then develop a decision tool to aid clinicians in selection of patients for first-line anti-IL-12/23 therapy. Then, we will investigate genomic predictors of response using both a targeted and genome wide approach. Finally, we will identify transcriptional modules which associate with drug response which will yield insight into the tissue cell signatures which associate with differential response. The scientific and training objectives outlined will provide me with the expertise needed to pursue independent investigation in the field of precision medicine, with a specific emphasis on the utilization of large scale clinical and genomic datasets to predict prognostic and therapeutic outcomes in CD.

抽象的 克罗恩病（CD）是一种慢性免疫介导的胃肠道疾病，其特征是 临床和分子异质性。疾病的广泛差异证明了临床异质性 位置，严重性和行为。众多遗传风险基因座证明了分子异质性 迄今已确定的。幸运的是，对于 CD的处理，包括肿瘤坏死因子的阻断和IL-12/23信号的阻断。 不幸的是，患者通常由于缺乏反应，进一步增加而迅速通过药物循环 发病率和医疗保健费用。因此，迫切需要数据与 疾病到治疗靶标，以指导治疗选择。我们的长期目标是改善一线治疗 随着更多的疗法以生物仿制品的价格获得CD的选择。在这个职业发展建议中，我 将着重于获取数据，该数据可深入了解临床和分子属性 与对抗IL-12/23疗法的反应相关的，以改善药物定位和一线治疗 在CD中选择此类治疗。我们已经表明CD患有自身免疫性皮肤疾病的患者 优先对抗IL-12/23治疗做出了反应。我们将利用机器学习来确定其他临床 与治疗优先反应相关的模式，然后开发一个决策工具，以帮助临床医生 选择一线抗IL-12/23治疗的患者。然后，我们将研究 使用靶向和基因组范围的方法响应。最后，我们将确定转录模块 与药物反应相关的，这将洞悉与组织细胞的特征相关的组织细胞特征 差异响应。概述的科学和培训目标将为我提供所需的专业知识 在精确医学领域进行独立调查，并特别强调利用 大规模的临床和基因组数据集，以预测CD中的预后和治疗结果。