权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

WAVE Regulatory Complex in Primary Immunodeficiency Disease and autoimmunity

原发性免疫缺陷病和自身免疫性疾病中的 WAVE 调节复合体

基本信息

批准号：
10789081
负责人：
BRIAN M IRITANI
金额：
$ 8.07万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10789081
关键词：
Actins Affect Antibody Formation Antibody Response Antibody-mediated protection Antigens Autoantibodies Autoimmunity B-Cell Activation B-Cell Antigen Receptor B-Cell Development B-Lymphocytes B-cell receptor repertoire sequencing Bacteremia Bacterial Infections Biological Models Bone Marrow CRISPR/Cas technology Cell physiology Cells ChIP-seq Characteristics Child Color Communities Complex Cre-LoxP Cytokine Receptors Development Diffusion Disease Exhibits Family Flow Cytometry Gene Expression Gene Targeting Genes Genetic Heterogeneity Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Hematopoietic Homeostasis Homing Homologous Protein Human Humoral Immunities Image Immune Immune Tolerance Immunity Immunization Immunoglobulin Class Switching Immunologic Deficiency Syndromes Immunologic Receptors Impairment Individual Infection Infectious Skin Diseases Inflammatory Bowel Diseases Influenza A virus Integrins Knowledge Ligation Link Lymphoid Malignant lymphoid neoplasm Mediating Microscopy Mission Modeling Molecular Mus Mutation Patients Plasma Cells Pneumococcal Pneumonia Point Mutation Polymers Predisposition Production Prognosis Proteins Public Health Receptor Signaling Recurrence Research Resolution Respiratory Tract Infections Role Signal Transduction Streptococcus pneumoniae System T-Cell Receptor T-Independent Antigens T-Lymphocyte Technology Testing Time Toll-like receptors United States National Institutes of Health Untranslated RNA Variant Virus Diseases autoreactivity cell type chemokine congenital immunodeficiency cytokine fly genetic regulatory protein genome wide association study human disease human model humanized mouse humoral immunity deficiency improved innovation loss of function loss of function mutation member migration mortality mouse model novel therapeutics pathogen polymerization premature respiratory pathogen response rho stem cells transcriptome transcriptome sequencing translational impact two-photon vaccination strategy

项目摘要

PROJECT SUMMARY Of the greater than 350 Primary Immunodeficiency Diseases (PID) in humans that have been identified to date, the molecular basis of a significant number (~100) of PIDs have yet to be defined. Recently, 9 children (4 now deceased) from 4 independent families were identified with severe PIDs that were linked to mutations in the NCKAP1L gene encoding for Hematopoietic protein-1 (Hem-1), a conserved hematopoietic cell-specific component the WAVE actin regulatory complex (WRC). Affected children presented with severe recurring respiratory and skin infections, failed antibody responses to pneumococcal immunization (characteristic of B cell immunodeficiency), dysregulated cytokine production, and autoimmunity. Although the cellular and molecular functions of Hem-1 orthologues in flies and worms are relatively well characterized, there is a critical knowledge gap regarding the cell specific functions of Hem-1 in the development and functions of primary immune cells. Our longterm goal is to overcome this knowledge gap by dissecting the cell-specific roles of Hem-1 in the development and functions of adaptive and innate immune cells. The objective of this proposal is to disrupt Hem-1 expression in primary murine and human B lymphocytes in a B cell-specific manner to define the roles of Hem-1 in B cell development, protective humoral immunity, and autoimmunity. Our Specific Aims are to utilize inducible B cell specific gene targeting in mice, and CRISPR/Cas9 mediated Hem1 deletion in “humanized mice”, to test our central hypotheses that B cell specific disruption in Hem1 results in: (1) impaired B cell development in part due to reduced homing and retention of developing B cell progenitors in essential lymphoid niches;(2) absent T cell independent antibody responses resulting in crippled protective immunity to influenza A virus and Streptococcus pneumoniae, important community acquired respiratory pathogens; and (3) hyper-responsive B cell signaling and T-bet driven transcriptome, resulting in increased autoantibody production. To demonstrate feasibility, we have generated innovative mouse models to emulate Hem1 PID patients including mice with a non-coding point mutation in Hem1 (Hem1pt/pt), Hem1 null (Hem1-/-) mice, Hem1floxed (Hem1fl/fl) mice, as well as Hem1 deficient ”humanized mice” which contain Hem1 deficient primary human hematopoietic cells. Based on our preliminary results which strongly support our hypotheses, we expect that the results of these studies will be highly significant and will have a high impact because they will define for the first time, the cellular and molecular mechanisms of how loss-of-function variants in NCLAP1L disrupt B cell development, signaling, and protective antibody-mediated immunity resulting in PID and autoimmunity. Because of extensive genetic heterogeneity of the 4 human PID families, limited number of patients, and concurrent infections, the development of these innovative mouse model systems are critical for dissecting the cellular and molecular mechanisms of how mutations in Hem-1 result in PID and autoimmunity, and to provide much needed platforms to develop and test therapies to treat and cure Hem1 deficient children.

项目总结