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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

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
项目类别：
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

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