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.

NK细胞缺乏症（NKD）是原发性免疫缺陷疾病的子集/免疫误差（IEI） NK细胞异常代表主要的临床免疫缺陷。异常NK细胞的患者 容易受到致命病毒感染和某些癌症的影响，为我们提供了一个独特的窗口 临界免疫细胞起作用。 15多年来，我们一直在照顾并调查了这些复杂的患者， 应用基因组技术发现严重的基因并照亮NK细胞生物学。在此应用程序中， 我们渴望更新我们协调的NKD发现计划，其最终目标是了解如何 照顾这些患者以及如何热使用NK细胞。在过去的5年中 程序，我们定义了2种NKD的新遗传原因，以及8种影响NK细胞的IEI新原因。我们 建立并建立了针对NKD患者的国际推荐网络，以临床和 免疫学上定义了这些罕见患者，使我们的基因组评估/发现途径成熟，并 优化以患者为中心的功能基因组学和NK细胞生物学技术，所有这些都是为了促进进展 了解NKD。目前，我们有156名患者参加了NK细胞评估和研究（近） 哥伦比亚的计划：其中有70个在贝勒医学院接受了外部测序（ES），13 已经发现了疾病的遗传溶液，有11个已确定的基因，而36个未被解析。 在这个续签期间，我们将以成功的势头为基础，将新的NKD患者添加到我们的 通过使用数据库在临床和免疫学上，从临床和免疫学上定义疾病的管道，先进 生物统计技术和研究水平表型和功能评估（AIM 1），增加了新的 基因组发现和分析技术，例如整个基因组测序和RNA测序，以带来 对于NKD基因保持“未解决”并应用尖端功能的患者的清晰度 基因组学和NK细胞生物学技术以证明基因突变的影响和相关性 发现（目标3）。我们利用了在领域内外的强大，长期合作的合作 免疫缺陷以最好地定义我们确定的基因突变如何影响NK细胞在 人类健康。这样一来，我们的目标不仅要更好地诊断和照顾这些复杂的患者，还要更好地照顾 更好地了解NK细胞如何保护人类免受病毒和癌症的影响。