GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY

人类 NK 细胞缺陷的遗传、免疫学和机制基础

• 批准号: 10363767
• 负责人: Jordan Scott Orange
• 金额: $ 78.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-19 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363767
• 关键词: Abnormal Cell; Affect; Biological; Biometry; CD34 gene; Candidate Disease Gene; Caring; Cell Line; Cell model; Cell physiology; Cells; Cellular Structures; Cellular biology; Cessation of life; Clinical; Collaborations; Complex; Computer Analysis; Databases; Defect; Development; Diagnosis; Disease; Enrollment; Etiology; Evaluation; Evaluation Research; Funding; Future; Gene Mutation; Genes; Genetic; Genetic Diseases; Genomic medicine; Genomics; Genotype; Goals; Grant; Health; Hereditary Disease; Human; Image; Immune; Immunity; Immunologic Deficiency Syndromes; Immunologics; Impairment; Infrastructure; International; Investigation; Knowledge; Laboratories; Learning; Light; MCM10 gene; Malignant Neoplasms; Mechanics; Medicine; Methods; Natural History; Natural Killer Cells; Pathway interactions; Patient Care; Patients; Phenotype; Positioning Attribute; Prognosis; Proteins; Research; Systems Development; Techniques; Testing; Therapeutic; Variant; Virus; Virus Diseases; Work; advanced analytics; base; cell killing; cohort; college; congenital immunodeficiency; data lake; diagnosis evaluation; exome sequencing; functional genomics; genome sequencing; improved; induced pluripotent stem cell; insight; interest; novel; phenotypic data; programs; recruit; success; transcriptome sequencing; whole genome

NK cell deficiency (NKD) is a subset of primary immunodeficiency diseases/inborn errors of immunity (IEI) in which the NK cell abnormality represents the main clinical immunodeficiency. Patients with abnormal NK cells are susceptible to lethal virus infections and certain cancers, offering us a unique window into how these critical immune cells work. For over 15 years we have cared for and investigated these complex patients, applying genomic techniques to discover causative genes and illuminate NK cell biology. With this application, we aspire to renew our coordinated NKD discovery program, with the ultimate goals of understanding how to care for these patients as well as how to best use NK cells therapeutically. Over the past 5 years of our program, we have defined 2 new genetic causes of NKD and 8 new causes of IEI that affect NK cells. We established and grew an international referral network for NKD patients, honed methods to clinically and immunologically define these rare patients, matured our genomic evaluation/discovery pathways, and optimized patient-focused functional genomics and NK cell biological techniques, all to advance progress in understanding NKD. At present, we have 156 patients enrolled in our NK cell evaluation and research (NEAR) program at Columbia: of these, 70 have undergone exome sequencing (ES) at Baylor College of Medicine, 13 have found genetic solutions for their disease, 11 have a promising gene identified, and 36 remain unsolved. During this renewal period, we will build on our successful momentum, adding new NKD patients to our pipeline, clinically and immunologically defining their disease through the use of databases, advanced biostatistical techniques and research level phenotypic and functional assessments (Aim 1), adding new genomic discovery and analytic techniques like whole genome sequencing and RNA sequencing to bring clarity to the patients whose NKD genes remain “unsolved” (Aim 2), and applying cutting-edge functional genomics and NK cell biological techniques to demonstrate the impact and relevance of the gene mutations we discover (Aim 3). We capitalize on strong, long-standing collaborations both within and beyond the field of Immunodeficiency in order to best define how the gene mutations we identify impact how NK cells function in human health. In so doing, we aim to not only better diagnose and care for these complex patients, but to better understand how NK cells protect humans from viruses and cancer.

自然杀伤细胞缺乏症(NKD)是人类免疫缺陷疾病/先天免疫缺陷(IEI)的一种亚型 其中NK细胞异常是临床免疫缺陷的主要代表。NK细胞异常的患者 容易受到致命的病毒感染和某些癌症的影响，这为我们提供了一个独特的窗口来了解这些 关键的免疫细胞起作用。15年多来，我们一直在关心和调查这些复杂的患者， 应用基因组学技术发现致病基因并阐明NK细胞生物学。使用此应用程序， 我们渴望更新我们的协调NKD发现计划，最终目标是了解如何 护理这些患者以及如何在治疗上最好地使用NK细胞。在过去的5年里，我们的 计划中，我们定义了NKD的2个新的遗传原因和8个影响NK细胞的IEI的新原因。我们 建立和发展NKD患者的国际转诊网络，磨练临床和 免疫学定义这些罕见的患者，成熟我们的基因组评估/发现途径，以及 优化的以患者为中心的功能基因组学和NK细胞生物技术，所有这些都是为了推动 了解NKD。目前，我们有156名患者参加了我们的NK细胞评估和研究(NEAR) 哥伦比亚大学的计划：其中70人在贝勒医学院接受了外显子组测序，13人 已经找到了他们疾病的基因解决方案，11人发现了有希望的基因，36人仍未解决。 在此续签期间，我们将继续发展我们的成功势头，将新的NKD患者加入我们的 流水线，通过使用数据库在临床和免疫学上确定他们的疾病，高级 生物统计技术和研究水平表型和功能评估(目标1)，增加新的 全基因组测序和RNA测序等基因组发现和分析技术将带来 明确NKD基因仍未解决的患者(目标2)，并应用尖端功能 基因组学和NK细胞生物学技术证明基因突变的影响和相关性 发现(目标3)。我们利用在以下领域内外的强大而长期的合作 免疫缺陷，以最好地定义我们识别的基因突变如何影响NK细胞在 人类健康。通过这样做，我们的目标不仅是更好地诊断和护理这些复杂的患者，而且 更好地了解NK细胞如何保护人类免受病毒和癌症的侵袭。