Pharmacogenomics of Adrenal Suppression with Inhaled Corticosteroids (PhASIC)

吸入皮质类固醇抑制肾上腺的药物基因组学 (PhASIC)

• 批准号: 10171899
• 负责人: Amber Dahlin
• 金额: $ 89.22万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171899
• 关键词: Acute; Address; Adrenal Cortex Hormones; Adrenal Glands; Adrenal gland hypofunction; Adverse effects; Adverse event; Amber; Asthma; Automobile Driving; Bayesian Network; Bioinformatics; Biological; Caring; Chronic Disease; Clinical; Clinical Trials; Complex; Computer Models; Consensus; Corticotropin; Data; Diagnostic tests; Disease; Doctor of Philosophy; Dose; Drug Exposure; Drug Prescriptions; Emergency department visit; Functional disorder; Future; General Population; Genes; Genetic; Genomics; Goals; Gold; Guidelines; Health Care Costs; Healthcare Systems; Hospitalization; Hydrocortisone; Individual; Inhalation; Investigation; Knowledge; Laboratories; Lead; Light; Link; Lung; Methods; Molecular; Monitor; Organ; Pathway interactions; Patient risk; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Plasma; Population; Production; Publications; Research; Resistance; Risk; Role; Sampling; Severities; Steroid Resistance; Steroids; Symptoms; Systems Biology; Testing; Treatment Protocols; Treatment outcome; Urine; Ursidae Family; Work; alternative treatment; asthma exacerbation; asthmatic; asthmatic patient; base; biobank; cost; economic value; experience; genome wide association study; hypothalamic-pituitary-adrenal axis; improved; improved outcome; individualized medicine; innovation; insight; inter-individual variation; metabolomics; molecular marker; network models; novel; personalized medicine; precision medicine; prevent; prospective; public health relevance; repository; research clinical testing; responders and non-responders; response; side effect; symptom management; treatment response

Pharmacogenomics of Adrenal Suppression with Inhaled Corticosteroids (PhASIC) Amber Dahlin PhD MMSc, Jessica Lasky-Su ScD, Ann Wu MD MPH, Kelan Tantisira MD MPH, Scott Weiss MD MPH Project Description Recent advances in systems biology have enabled the identification of molecular predictors of treatment outcomes for complex diseases, including asthma. Asthma is one of the most common chronic diseases in the world, and inhaled corticosteroids are routinely prescribed medications for management of symptoms. While generally well tolerated, the long-term use of corticosteroids can elicit serious side effects, including adrenal suppression, an important adverse event with the potential to lead to acute adrenal crisis due to suppression of cortisol. As 30% or more of asthma patients experience poor steroid responsiveness and require increased doses to control asthma symptoms, these patients are at increased risk of developing adrenal suppression. Both corticosteroid responsiveness and adrenal suppression demonstrate repeatable inter-individual variation that is partly due to genetics; however, the genetic and molecular contributions to both steroid response and adrenal suppression are not well understood. Given the potential severity of poor responsiveness to corticosteroids, the ability of clinicians to predict how asthma patients may respond could mitigate unnecessary drug exposure and reduce the risk of side effects, including adrenal suppression. This innovation could ultimately allow clinicians to tailor treatment regimens more precisely to avoid adverse events, thereby addressing an unmet clinical need. Pharmacogenomics bears the promise to improve asthma care, and focusing on identifying the molecular ‘drivers’ of corticosteroid response could significantly improve treatment outcomes for patients. The goal of this study is to identify the genes and metabolites that contribute to steroid responsiveness in asthma. We will clarify the molecular drivers of steroid resistance in asthma using an innovative, systems biology-based approach that integrates genomic and metabolomic profiling of large populations with predictive computational modeling, making the discovery of biologic implications of treatment response more likely, as no single ‘omics’ approach is likely to lead to translatable findings. These molecular predictors could ultimately comprise a future clinical or diagnostic test to advance precision medicine efforts for asthma treatment. In addition, through this research effort, we will increase understanding of how adverse events such as adrenal suppression are linked to treatment outcomes. This work is anticipated to provide novel information to drive new treatment paradigms and, ultimately, improve patient risk profiles for asthma.

吸入皮质类固醇抑制肾上腺激素的药物基因组学（PhASIC） Amber Dahlin PhD MMSC，Jessica Lasky-Su ScD，Ann Wu MD MPH，Kelan Tantisira MD MPH，Scott韦斯 MD MPH 项目描述 系统生物学的最新进展使得能够识别治疗的分子预测因子 包括哮喘在内的复杂疾病的结果。哮喘是最常见的慢性疾病之一， 吸入性皮质类固醇是用于控制症状的常规处方药物。而 一般耐受性良好，长期使用皮质类固醇可引起严重的副作用，包括肾上腺皮质激素， 抑制，一种重要的不良事件，由于抑制 皮质醇由于30%或更多的哮喘患者的类固醇反应性差，需要增加 这些患者有增加肾上腺抑制的风险。 皮质类固醇反应性和肾上腺抑制均表现出可重复的个体间差异 这部分是由于遗传学;然而，遗传和分子的贡献类固醇反应和 肾上腺抑制还不太清楚。 考虑到对皮质类固醇反应性差的潜在严重性，临床医生预测其反应性的能力 哮喘患者可以缓解不必要的药物暴露并降低副作用的风险， 包括肾上腺抑制。这项创新最终可以让临床医生定制治疗方案 更准确地说是为了避免不良事件，从而解决未满足的临床需求。药物基因组学熊 改善哮喘护理的承诺，并专注于确定皮质类固醇的分子“驱动因素” 反应可以显着改善患者的治疗结果。 这项研究的目的是确定基因和代谢物，有助于类固醇反应， 哮喘我们将使用一种创新的系统， 一种基于生物学的方法，该方法整合了大量人群的基因组学和代谢组学分析， 计算建模，使治疗反应的生物学意义的发现更有可能，因为没有 单一的“组学”方法很可能导致可翻译的发现。这些分子预测因子最终可以 包括未来的临床或诊断测试，以推进哮喘治疗的精确医学努力。在 此外，通过这项研究工作，我们将增加对肾上腺皮质激素等不良事件的了解， 抑制与治疗结果有关。这项工作预计将提供新的信息，以推动 新的治疗模式，并最终改善哮喘患者的风险状况。