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)

基本信息

批准号：
10620657
负责人：
Amber Dahlin
金额：
$ 89.13万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10620657
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 Guidelines Health Care Costs Healthcare Systems Hospitalization Hydrocortisone Individual Inhalation Knowledge Laboratories Light Link Lung Methods Molecular Monitor Organ Pathway interactions Patient risk Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacogenomics Phenotype Plasma Population Prediction of Response to Therapy Production Public Health Publications Recommendation Research Resistance Risk Risk Reduction Role Sampling Severities Steroid Resistance Steroids Symptoms Systems Biology Testing Translational Research Treatment Protocols Treatment outcome Urine Work alternative treatment asthma exacerbation asthmatic asthmatic patient 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 repository research clinical testing responders and non-responders response side effect symptom management treatment response

项目摘要

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的药物基因组学 (PhASIC) Amber Dahlin 博士 MMSc、Jessica Lasky-Su ScD、Ann Wu MD MPH、Kelan Tantisira MD MPH、Scott Weiss 医学博士公共卫生硕士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是最常见的慢性疾病之一。世界各地，吸入皮质类固醇是治疗症状的常规药物。通常耐受性良好，长期使用皮质类固醇会引起严重的副作用，包括肾上腺皮质激素抑制，一种重要的不良事件，有可能由于抑制而导致急性肾上腺危象 30% 或更多的哮喘患者对类固醇反应较差，需要增加皮质醇。控制哮喘症状的剂量，这些患者发生肾上腺抑制的风险增加。皮质类固醇反应性和肾上腺抑制都表现出可重复的个体间差异这部分是由于遗传因素；然而，遗传和分子对类固醇反应和肾上腺抑制尚不十分清楚。鉴于对皮质类固醇反应不良的潜在严重性，信徒有能力预测如何哮喘患者可能会做出反应，可以减少不必要的药物暴露并降低副作用的风险，包括肾上腺抑制，这一创新最终可以实现定制治疗方案。更准确地避免不良事件，从而解决药物基因组学方面未满足的临床需求。改善哮喘护理的承诺，并专注于识别皮质类固醇的分子“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有助于类固醇反应的基因和代谢物我们将使用创新系统阐明哮喘类固醇耐药的分子驱动因素。基于生物学的方法，将大量人群的基因组和代谢组学分析与预测相结合计算模型，使得更有可能发现治疗反应的生物学影响，因为没有单一的“组学”方法可能最终会带来可转化的发现。包括未来的临床或诊断测试，以推进哮喘治疗的精准医学工作。此外，通过这项研究工作，我们将加深对肾上腺等不良事件如何发生的了解。抑制与治疗结果相关，这项工作预计将提供新的信息来驱动。新的治疗模式，并最终改善患者的哮喘风险状况。