Genetic Risk Underlying Pediatric Critical Illness

儿科危重疾病的遗传风险

• 批准号: 10739999
• 负责人: Joshua Ethan Motelow
• 金额: $ 25.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739999
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Adverse drug event; Asthma; Biological; Caring; Child; Childhood; Chronic Kidney Failure; Clinical; Clinical Management; Clinical Trials; Clinical stratification; Critical Care; Critical Illness; Critically ill children; Data; Databases; Disease; Doctor of Philosophy; Dose; Early Intervention; Enrollment; Environment; Equity; Fellowship; Future; Genes; Genetic; Genetic Risk; Genetics and Medicine; Genome; Genomics; Goals; Hereditary Disease; Heterogeneity; Human Genetics; Hypersensitivity; Immunity; Intervention; Kidney; Lead; Light; Lower Respiratory Tract Infection; Mediating; Medical center; Medicine; Mendelian disorder; Mentors; Mentorship; Methods; Morbidity - disease rate; Network-based; Neurosciences; Oranges; Pathway interactions; Patients; Pediatric Intensive Care Units; Pharmaceutical Preparations; Pharmacogenomics; Phenotype; Physicians; Positioning Attribute; Postdoctoral Fellow; Predisposition; Proteins; Publishing; Research; Resources; Respiratory Failure; Risk; Risk Factors; Sample Size; Sampling; Scientist; Secondary to; Source; Testing; Time; Training; Universities; Variant; Viral; Virus Diseases; career development; clinical risk; clinically actionable; cohort; comparative efficacy; comparison control; disorder risk; ethical, legal, and social implication; exome; exome sequencing; experimental study; gene network; genetic association; genome sequencing; improved; innovation; loss of function; medication administration; next generation sequencing; novel; novel therapeutics; polygenic risk score; precision medicine; programs; response; risk variant; targeted treatment; therapeutic development; venous thromboembolism

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.

项目总结/摘要 孩子很少会得重病。我假设遗传风险导致了意想不到的儿科危重病， 病识别风险组可以进行临床分层和靶向治疗，但这些益处可能 只有在知道风险的情况下才能实现。该提案将揭示单基因（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）的风险 病危在目标1中，我应用创新的基因网络发现方法来揭示病毒感染的单基因风险。 呼吸衰竭是儿科重症监护病房最常见的原因。在目标2中，我将评估 多基因风险对常见儿科重症监护病房发病率（病毒性呼吸衰竭， 静脉血栓栓塞、急性肾损伤）。在目标3中，我将评估通过以下方法检测到的药物基因组学风险： 外显子组和基因组测序。K 08将揭示危重儿童的遗传风险， 未来的多中心遗传关联研究和临床试验，以改善儿科重症监护的护理 单位候选人：科学家，我有神经科学博士学位，并在年完成了博士后研究。 人类遗传学。临床上，我是一名儿科重症监护医学的主治医师。有必要 医生科学家谁可以识别不寻常的疾病介绍和发现新的遗传风险。有 精准医疗在儿科重症监护病房的应用有限，我很有能力识别 机会和调查应用。我的目标是开发一个独立的研究项目， 儿科危重病的基因组学在K 08培训期间，我将：（1）完善基因方面的专业知识 网络发现，（2）发展多基因风险评分在儿童中的新应用的专业知识， 危重病，（3）发展外显子组和基因组的药物基因组学分析的专业知识，（4）成为 精通基因组学的伦理、法律的和社会影响（ELSI）;（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队伍。 遗传学和医学专家团队（导师Gharavi博士和顾问Chung博士），多基因风险评分 (Dr. Kiryluk，顾问），药物基因组学（Jobanputra博士，顾问和Chung博士，顾问），统计学 遗传学（Ionita-Laza博士，顾问），过敏和先天性免疫缺陷（橙子博士，顾问），肾遗传学 (Dr. Gharavi，Mentor和Kiryluk博士，顾问），以及公平和ELSI研究（Sabatello博士，顾问）。的 研究将在哥伦比亚大学欧文医学中心进行，这将使我能够访问 广泛的资源和培训，帮助我成功地过渡到独立。