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.

项目摘要/摘要 孩子很少患病。我假设遗传风险导致了意外的小儿关键 确定风险组允许进行临床分层和有针对性的疗法，但是这些好处可以 仅在知道风险的情况下才能意识到。该建议将发现单基因（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作用）有促进小儿的风险 重症病。在AIM 1中，我应用创新的基因网络发现方法来发现病毒的单基因风险 呼吸衰竭，这是小儿重症监护病房入院的最常见原因。在AIM 2中，我将评估 多基因风险对普通小儿重症监护病房的贡献（病毒呼吸衰竭， 静脉血栓栓塞，急性肾脏损伤）。在AIM 3中，我将评估由 外显子组和基因组测序。该K08将发现重症儿童的遗传风险，这将告知 未来的多中心遗传关联研究和临床试验，以改善小儿重症监护 单元。候选人：从科学上讲，我拥有神经科学博士学位，并完成了博士后奖学金 人类遗传学。临床上，我是小儿重症监护医学的身体。需要 可以识别异常疾病表现并发现新颖遗传风险的身体科学家。有 精确医学在小儿重症监护病房中的应用有限，我有好处确定 机会并调查申请。我的目标是制定一个专注于 “小儿危害疾病的基因组学”。在K08培训期间，我将：（1）完善基因专业知识 网络发现，（2）在新的多基因风险分数对儿童的新颖应用中发展专业知识 危害疾病，（3）在外部和基因组的药物基因组学分析方面发展专业知识，（4）成为 熟练掌握基因组学的道德，法律和社会含义（ELSI），以及（5）过渡到独立性。 环境：为了指导和支持我的研究和培训目标，我集会了强烈的心态 遗传学和医学专家团队（Gharavi博士，导师和Chung博士，顾问），多基因风险分数 （顾问Kiryluk博士），药物基因组学（Jobanputra博士，顾问和Chung博士，顾问），统计 遗传学（Ionita-Laza博士，顾问），免疫过敏和天生的免疫错误（Orange，Advisor博士），肾脏遗传学 （顾问Gharavi博士，顾问Kiryluk博士）以及Equity and Elsi Research（Sabatello博士，顾问）。这 研究将在哥伦比亚大学欧文医学中心进行，这将使我访问 广泛的资源和培训，以帮助我成功过渡到独立性。