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HIPK1: a new immunomodulatory target for SLE

HIPK1：SLE 的新免疫调节靶点

基本信息

批准号：
10647292
负责人：
ANDREW D WELLS
金额：
$ 26.7万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647292
关键词：
3-Dimensional Affect Affinity American Antibodies Antibody Formation Antibody Response Antigens Autoantibodies Autoimmune Diseases Autoimmunity B cell differentiation B-Lymphocytes BCL6 gene BLR1 gene Biology Blood Cell Lineage Cell Nucleus Cells Chickens Chromosome Mapping Clustered Regularly Interspaced Short Palindromic Repeats Code Collaborations Communicable Diseases Development Disease Drug Modulation Drug Targeting Enzymes Foundations Functional disorder Future Generations Genes Genetic Genetic Polymorphism Genetic Variation Genetic study Genome Genomics Health Helper-Inducer T-Lymphocyte Homeostasis Human Humoral Immunities IL7R gene Immune Immune response Immunity Immunization Immunoglobulin Class Switching Immunomodulators Immunophenotyping In Vitro Infection Inflammation Inherited Knockout Mice LoxP-flanked allele Lupus Lymphocyte Lymphoid Malignant Neoplasms Maps Mediating Modeling Molecular Morbidity - disease rate Mus Mutation Organoids Outcome Outcome Study Ovalbumin Patients Pharmacology Study Phosphotransferases Predisposition Production Publishing Regulation Regulatory Element Role Series Structure of germinal center of lymph node System Systemic Lupus Erythematosus T cell differentiation T cell regulation T-Cell Development T-Lymphocyte TLR7 gene Testing Tonsil Untranslated RNA Vaccination Vaccines Variant Work adaptive immunity antigen-specific T cells autoinflammatory diseases cell type cytokine efficacy study gain of function genome wide association study high risk human model immunoregulation in vivo insight interleukin-21 loss of function mortality mouse model mutant novel novel therapeutic intervention pediatric patients pharmacologic programmed cell death protein 1 response single-cell RNA sequencing systemic autoimmune disease systemic inflammatory response three dimensional structure transcriptomics variant of unknown significance women of color young woman

项目摘要

ABSTRACT Our prior work using physical maps of systemic lupus erythematosus (SLE)-associated genetic variation in the context of the 3D structure of the genome in the nucleus of disease-relevant immune cell types have implicated the kinase HIPK1 as a factor controlling SLE susceptibility. This kinase has been studied in the context of cancer, but a role for HIPK1 in immunity, tolerance, or SLE has not been explored. In this exploratory, high-risk/high- impact application we will use genetic and pharmacologic targeting approaches to establish whether HIPK1 regulates T cell differentiation, T cell-dependent humoral immune responses, and SLE pathophysiology in powerful human and mouse models of follicular lymphocyte differentiation and function. The outcome of these studies is likely to forward basic understanding of the regulation of humoral immunity and suggest a completely novel immunomodulatory approach for the management of SLE disease.

摘要我们之前的工作使用了系统性红斑狼疮(SLE)相关遗传变异的物理图谱与疾病相关的免疫细胞类型的核中基因组的3D结构的背景已经暗示激酶HIPK1作为控制SLE易感性的因素。这种激酶已经在癌症的背景下进行了研究，但HIPK1在免疫、耐受或系统性红斑狼疮中的作用尚未被探索。在这种探索性、高风险/高- 我们将使用遗传和药理学靶向方法来确定HIPK1是否调节T细胞分化、T细胞依赖的体液免疫反应和SLE的病理生理学人和小鼠滤泡淋巴细胞分化和功能的强大模型。这些措施的结果研究可能会促进对体液免疫调节的基本理解，并建议完全治疗系统性红斑狼疮疾病的新免疫调节方法。