Novel Primary Immunodeficiency Disease Due to IL27RA Deficiency

IL27RA 缺乏导致的新型原发性免疫缺陷病

基本信息

批准号：
10311550
负责人：
Lisa Forbes
金额：
$ 20.06万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-03 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311550
关键词：
Address Affect Biological Response Modifiers CD4 Positive T Lymphocytes CD8B1 gene CRISPR/Cas technology Cell Line Cell Proliferation Cell physiology Cells Clinical Complement Control Groups Data Data Discovery Defect Diagnosis Disease Enzyme-Linked Immunosorbent Assay Etiology Family Flow Cytometry Fostering Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genomics Goals Granuloma Health Hereditary Disease Human IL27RA gene IL6ST gene Immune response Immunity Immunogenetics Immunologic Deficiency Syndromes Immunologics Impairment Interleukin-13 Interleukin-17 Interleukin-4 Interleukin-6 Interleukins Investigation Knowledge Life Lymphopenia Measures Membrane Memory Messenger RNA Mission Molecular Morbidity - disease rate Mus Otitis Media Outcome Output Pathogenicity Pathway interactions Patients Peripheral Blood Mononuclear Cell Phenotype Phosphorylation Play Population Process Production Protocols documentation Public Health Recurrence Research Reverse Transcriptase Polymerase Chain Reaction Role STAT1 gene STAT3 gene Signal Transduction Stat5 protein T cell differentiation T memory cell T-Lymphocyte TNF gene Technology Telomerase Testing Th1 Cells Th2 Cells United States National Institutes of Health Variant Western Blotting Work burden of illness causal variant clinical phenotype congenital immunodeficiency cytokine disability exome sequencing experimental group high risk human disease improved individualized medicine innovation insight lentivirally transduced loss of function magnetic beads mortality mutant nano-string novel prevent proband programs protein expression receptor retroviral transduction variant of unknown significance

项目摘要

Defects in over 400 genes have been identified as causes of primary immunodeficiency diseases. The molecular etiologies of many primary immunodeficiency diseases nevertheless remain unknown. This gap in knowledge impairs our ability to diagnose and properly treat affected patients. A critical need therefore exists for enhanced understanding of the genetic basis and mechanisms of primary immunodeficiency diseases. The objective of this application is to use cutting-edge genomic and molecular technologies to investigate a novel primary immunodeficiency disease, [GRAnulomas, Low T cells, and Short stature (GRALTS)], associated with biallelic pathogenic variants in IL27RA. The central hypothesis of this application is that IL27RA deficiency causes GRALTS. This hypothesis will be tested with 3 specific aims: 1) To define the effect of the variants on IL27RA expression in T cells, 2) To determine the impact of the variants on IL27RA function in T cells, and 3) Elucidate the downstream outcomes of impaired IL-27 signaling. The proposed work is innovative because defects in IL-27 signaling have not previously been shown to cause human disease. It is significant because it will validate IL27RA deficiency as a novel underlying cause of human primary immunodeficiency disease. Thus, this project is expected to have an important positive impact because it will augment our ability to appropriately recognize and treat primary immunodeficiency disease patients who have IL27RA deficiency. The information gained is anticipated to improve our ability to functionally assess and validate biallelic variants of uncertain significance in IL27RA and enhance our understanding of the importance of IL-27 signaling in human T cell function. The proposed research is therefore relevant to the mission of the NIH and this RFA because it focuses upon the investigation of a novel cause of human disease to gain fundamental knowledge that will facilitate reduction in the burden of illness and disability and improvement in the lives of patients who have this condition and related primary immunodeficiency diseases.

超过400个基因的缺陷已被确定为原发免疫缺陷疾病的原因。这然而，许多原发性免疫缺陷疾病的分子病因仍然未知。这个差距知识会损害我们诊断和适当治疗患者的能力。因此存在批判性需求为了增强对原发免疫缺陷疾病的遗传基础和机制的理解。这该应用的目的是使用尖端的基因组和分子技术来研究一种新型原发性免疫缺陷疾病，[肉芽瘤，低T细胞和矮小的身材（Gralts）]，与 IL27RA中的双重病原变体。该应用的中心假设是IL27RA缺乏症导致gralts。该假设将以3个特定目的进行检验：1）定义变体的效果在T细胞中的IL27RA表达上，2）确定变体对T细胞中IL27RA功能的影响， 3）阐明IL-27信号受损的下游结果。拟议的工作是创新的因为以前尚未证明IL-27信号传导中的缺陷会引起人类疾病。这很重要因为它将验证IL27RA缺乏症是人类原发性免疫缺陷的新基本原因疾病。因此，预计该项目将产生重要的积极影响，因为它将增强我们的能力适当识别和治疗患有IL27RA缺乏症的原发性免疫缺陷疾病患者。预计获得的信息将提高我们在功能上评估和验证双重变体的能力在IL27RA中具有不确定的意义，并增强了我们对IL-27信号在中的重要性的理解人类T细胞功能。因此，拟议的研究与NIH的使命和RFA有关因为它重点是研究人类疾病的新原因以获得基本知识这将有助于减轻疾病和残疾负担，并改善患者的生活患有这种情况和相关的原发性免疫缺陷疾病。