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.

抽象的我们之前的工作使用系统性红斑狼疮 (SLE) 相关遗传变异的物理图谱疾病相关免疫细胞类型细胞核中基因组 3D 结构的背景暗示了激酶 HIPK1 作为控制 SLE 易感性的因素。这种激酶已在癌症背景下进行了研究，但 HIPK1 在免疫、耐受或 SLE 中的作用尚未被探索。在这个探索性的、高风险/高- 我们将使用遗传和药理学靶向方法来确定 HIPK1 是否影响应用调节 T 细胞分化、T 细胞依赖性体液免疫反应和 SLE 病理生理学滤泡淋巴细胞分化和功能的强大人类和小鼠模型。这些的结果研究可能会增进对体液免疫调节的基本理解，并提出一个完整的方法用于治疗 SLE 疾病的新型免疫调节方法。