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

基本信息

项目摘要

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/先天性免疫缺陷(IEI)的一个子集, 其中NK细胞异常代表了主要的临床免疫缺陷。NK细胞异常患者 易受致命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,让我们了解这些疾病是如何发生的。 关键的免疫细胞起作用。15年来,我们一直在照顾和研究这些复杂的病人, 应用基因组技术发现致病基因并阐明NK细胞生物学。有了这个应用程序, 我们渴望更新我们协调的NKD发现计划,最终目标是了解如何 这些患者的护理以及如何最好地使用NK细胞治疗。在过去的5年里, 在该项目中,我们定义了影响NK细胞的2种新的NKD遗传原因和8种新的IEI原因。我们 建立并发展了NKD患者的国际转诊网络, 免疫学定义这些罕见患者,成熟了我们的基因组评估/发现途径, 优化以患者为中心的功能基因组学和NK细胞生物学技术,所有这些都是为了推动 了解NKD目前,我们有156名患者参加了我们的NK细胞评价和研究(NEAR) 哥伦比亚大学的一个项目:其中70个已经在贝勒医学院进行了外显子组测序(ES),13个 已经找到了他们疾病的遗传解决方案,11个已经确定了一个有希望的基因,36个仍然没有解决。 在此更新期间,我们将在成功势头的基础上,为我们的患者增加新的NKD患者 管道,临床和免疫学定义他们的疾病,通过使用数据库,先进的 生物统计技术和研究水平的表型和功能评估(目标1),增加新的 基因组发现和分析技术,如全基因组测序和RNA测序, 明确其NKD基因仍然“未解决”的患者(目标2),并应用尖端功能性 基因组学和NK细胞生物学技术来证明基因突变的影响和相关性, 发现(目标3)。我们充分利用在以下领域内外的强大、长期的合作: 免疫缺陷,以便最好地定义我们识别的基因突变如何影响NK细胞在免疫缺陷中的功能。 人体健康通过这样做,我们的目标不仅是更好地诊断和照顾这些复杂的病人, 更好地了解NK细胞如何保护人类免受病毒和癌症的侵害。

项目成果

期刊论文数量(28)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
  • DOI:
    10.1084/jem.20190147
  • 发表时间:
    2019-12-01
  • 期刊:
  • 影响因子:
    15.3
  • 作者:
    Lam, Michael T.;Coppola, Simona;Tartaglia, Marco
  • 通讯作者:
    Tartaglia, Marco
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Jordan Scott Orange其他文献

Jordan Scott Orange的其他文献

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{{ truncateString('Jordan Scott Orange', 18)}}的其他基金

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
  • 财政年份:
    2016
  • 资助金额:
    $ 76.95万
  • 项目类别:
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:
    10490860
  • 财政年份:
    2016
  • 资助金额:
    $ 76.95万
  • 项目类别:
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:
    9205454
  • 财政年份:
    2016
  • 资助金额:
    $ 76.95万
  • 项目类别:
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:
    9003675
  • 财政年份:
    2016
  • 资助金额:
    $ 76.95万
  • 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
  • 批准号:
    8308767
  • 财政年份:
    2011
  • 资助金额:
    $ 76.95万
  • 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
  • 批准号:
    7875101
  • 财政年份:
    2009
  • 资助金额:
    $ 76.95万
  • 项目类别:
The mechanism of NK cell defects in human NEMO deficiency
人类NEMO缺陷导致NK细胞缺陷的机制
  • 批准号:
    7629124
  • 财政年份:
    2008
  • 资助金额:
    $ 76.95万
  • 项目类别:
The mechanism of NK cell defects in human NEMO deficiency
人类NEMO缺陷导致NK细胞缺陷的机制
  • 批准号:
    7530223
  • 财政年份:
    2008
  • 资助金额:
    $ 76.95万
  • 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
  • 批准号:
    7650556
  • 财政年份:
    2008
  • 资助金额:
    $ 76.95万
  • 项目类别:
Directing Function at the Natural Killer Cell Secretory Immunological Synapse
自然杀伤细胞分泌免疫突触的指导功能
  • 批准号:
    8448575
  • 财政年份:
    2007
  • 资助金额:
    $ 76.95万
  • 项目类别:

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