Genetic Risk Underlying Pediatric Critical Illness

项目摘要/摘要 孩子们很少会得重病。我假设遗传风险会导致意外的儿科危重 生病了。识别风险组可以进行临床分层和靶向治疗，但这些好处可以 只有在知道风险的情况下才能实现。这一提议将揭示单基因(即单基因)、多基因(即， 许多基因)和药物基因组学(即对药物反应的遗传效应)风险导致儿科 得了重病。在目标1中，我应用创新的基因网络发现方法来揭示病毒的单基因风险。 呼吸衰竭是儿科重症监护病房入院的最常见原因。在目标2中，我将评估 多基因风险对儿科常见重症监护病房发病率的贡献(病毒性呼吸衰竭， 静脉血栓栓塞症、急性肾损伤)。在目标3中，我将评估检测到的药物基因组风险 外显子组和基因组测序。这份K08将揭示危重儿童的遗传风险，这将使 未来多中心基因关联研究和临床试验以改善儿科重症监护中的护理 单位。候选人：在科学方面，我拥有神经科学博士学位，并于年完成博士后研究 人类遗传学。在临床上，我是儿科重症监护医学的主治医生。有必要 内科医生-能够识别不寻常的疾病表现并发现新的遗传风险的科学家。的确有 精准医学在儿科重症监护病房的有限应用，我很有能力确定 机会和调查应用程序。我的目标是开发一个独立的研究项目，专注于 《儿科危重疾病的基因组学》。在K08培训期间，我将：(1)完善基因专业知识 网络发现，(2)开发多基因风险评分在儿童中的新应用方面的专业知识 危重疾病，(3)发展外显体和基因组的药物基因组分析专业知识，(4)成为 精通基因组学的伦理、法律和社会影响(ELSI)，以及(5)向独立过渡。 环境：为了指导和支持我的研究和培训目标，我组建了一个强大的导师 遗传学和医学专家团队(Gharavi博士，导师和钟博士，顾问)，多基因风险评分 (顾问Kiryluk博士)，药物基因组学(Jobanputra博士顾问和钟博士顾问)，统计学 遗传学(Ionita-Laza博士，顾问)、过敏和免疫先天错误(Orange博士，顾问)、肾脏遗传学 (Gharavi博士，导师和Kiryluk博士，顾问)，以及Equity和ELSI研究(Sabatello博士，顾问)。这个 研究将在哥伦比亚大学欧文医学中心进行，这将使我能够 广泛的资源和培训帮助我成功地过渡到独立。

Project Summary/Abstract Children rarely become critically ill. I hypothesize that genetic risk contributes to unexpected pediatric critical illness. Identifying risk groups allows for clinical stratification and targeted therapies, but these benefits can only be realized if risk is known. This proposal will uncover the monogenic (i.e., single gene), polygenic (i.e., many genes), and pharmacogenomic (i.e., genetic effect on drug response) risks contributing to pediatric critical illness. In Aim 1, I apply innovative gene-network discovery methods to uncover monogenic risk for viral respiratory failure, the most common cause of pediatric intensive care unit admission. In Aim 2, I will assess the contribution of polygenic risk to common pediatric intensive care unit morbidities (viral respiratory failure, venous thromboembolism, acute kidney injury). In Aim 3, I will assess pharmacogenomic risk detected by exome and genome sequencing. This K08 will uncover genetic risk in critically ill children which will inform future multi-center genetic association studies and clinical trials to improve care in the pediatric intensive care unit. Candidate: Scientifically, I have a PhD in neuroscience and completed a post-doctoral fellowship in human genetics. Clinically, I am an attending physician in pediatric critical care medicine. There is a need for physician-scientists who can identify unusual disease presentations and uncover novel genetic risk. There is limited application of precision medicine in the pediatric intensive care unit, and I am well positioned to identify opportunities and investigate applications. My goal is to develop an independent research program focused on “the genomics of pediatric critical illness”. During the K08 training period, I will: (1) Refine expertise in gene network discovery, (2) Develop expertise in the novel application of polygenic risk scores to children with critical illness, (3) Develop expertise in pharmacogenomic analysis of exomes and genomes, (4) Become proficient in the Ethical, Legal, and Social Implications (ELSI) of genomics, and (5) Transition to independence. Environment: To guide and support my research and training goals, I have assembled a strong mentorship team of experts in genetics and medicine (Dr Gharavi, Mentor and Dr. Chung, Advisor), polygenic risk scores (Dr. Kiryluk, Advisor), pharmacogenomics (Dr. Jobanputra, Advisor and Dr. Chung, Advisor), statistical genetics (Dr. Ionita-Laza, Advisor), allergy and inborn errors of immunity (Dr. Orange, Advisor), renal genetics (Dr. Gharavi, Mentor and Dr. Kiryluk, Advisor), and Equity and ELSI research (Dr. Sabatello, Advisor). The research will be conducted at Columbia University Irving Medical Center, which will give me access to extensive resources and training to help me successfully transition to independence.