Molecular Regulation of B cells and T cells in Human SLE

人类 SLE 中 B 细胞和 T 细胞的分子调控

基本信息

批准号：
10265746
负责人：
Ignacio E. Sanz
金额：
$ 56.09万
依托单位：
EMORY UNIVERSITY
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：
2020-07-06 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265746
关键词：
Antigens Antitumor Response Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity B cell differentiation B-Cell Development B-Lymphocytes Biological Markers CD8-Positive T-Lymphocytes Cancer Patient Categories Cell physiology Cells Chronic Clinical Clinical Protocols Clinical Research Collaborations Committee Members Comparative Study Development Diagnosis Disease Effector Cell Epigenetic Process Evolution Funding Genetic Predisposition to Disease Goals Heterogeneity Human Immune Immune checkpoint inhibitor Immune response Immunologics Individual Knowledge Lead Leadership Location Lupus Maintenance Mission Molecular Onset of illness Outcome PD-1 blockade Pathogenesis Pathogenicity Pathway interactions Patients Physicians Pilot Projects Population Process Regulation Resources Scientist Systemic Lupus Erythematosus T-Lymphocyte Translating Universities Virus Diseases Work arm autoreactive B cell base clinical development design epigenetic regulation epigenome exhaustion experience immunogenic imprint innovation novel operation personalized medicine programs response self-renewal stem stem-like cell

项目摘要

The overarching objective of the Emory Autoimmunity Center of Excellence (ACE) U19 is to decipher the molecular programs responsible for the aberrant effector immune responses that lead to autoimmune disease. Specifically, based on the work performed by the Emory ACE during the current funding cycle, we postulate that epigenetic regulation of effector B cell differentiation and function is a critical pathogenic component of Systemic Lupus Erythematosus (SLE). Further, we contend that disease-related epigenetic imprinting is first established at early stages of B cell development and then maintained throughout the differentiation of naïve cells into their effector progeny upon activation by antigens and co- stimulatory pathways. Finally, we propose that SLE will also be characterized by abnormal regulation of other critical effector immune responses, namely CD8 T cells and in particular, the stem-like population responsible for the maintenance of antigen-specific responses in chronic viral infections and anti-tumor responses in patients treated with checkpoint inhibitors. The fundamental goals of the Emory ACE are: 1) to understand B cells and CD8 T cells dysregulation in human SLE; and 2) to assemble a scientific and technological platform that engages other ACE U19 and UM1 Centers to perform similar studies in other immune cells and autoimmune disorders. The specific aims of the Emory ACE U19 are: Aim 1: To establish an Administrative Core (I. Sanz, Core Director) for the successful operation of the ACE U19 Scientific Program and its interaction with the ACE Network; Aim 2: To develop a highly integrated Emory ACE U19 Scientific Program comprised of the following components: Principal Project (Sanz, PI): Mechanisms of B cell dysregulation in human SLE; Collaborative Project (Boss, PI): Epigenetic regulation of autoimmune responses; Pilot Project (Ahmed, PI): Characterization of stem-like CD8 T cells in SLE. The expected results will unravel disease pathogenesis; segment patients; design personalized therapies; and develop biomarkers of disease onset, evolution, and outcome. Our efforts will naturally dovetail with the mission of the UM1 ACEs centers and contribute greatly to the charter mission of the ACE network.

埃默里自身免疫卓越中心 (ACE) U19 的总体目标是破译导致异常效应免疫反应的分子程序具体来说，根据埃默里大学 ACE 所做的工作。在当前的资助周期内，我们假设效应 B 细胞的表观遗传调控分化和功能是系统性狼疮的关键致病成分此外，我们认为与疾病相关的表观遗传印记是第一位的。在 B 细胞发育的早期阶段建立，然后在整个过程中维持初始细胞在被抗原和共激活物激活后分化为其效应子代最后，我们提出 SLE 也有异常的特征。调节其他关键效应免疫反应，即 CD8 T 细胞，特别是负责维持抗原特异性反应的干细胞群使用检查点抑制剂治疗的患者的慢性病毒感染和抗肿瘤反应。 Emory ACE 的基本目标是： 1) 了解 B 细胞和 CD8 T 细胞人类 SLE 失调；2) 建立一个科技平台，与其他 ACE U19 和 UM1 中心合作，对其他免疫细胞进行类似的研究埃默里 ACE U19 的具体目标是：目标 1：建立行政核心（I. Sanz，核心总监）负责 ACE U19 的成功运作科学计划及其与 ACE 网络的互动；目标 2：开发高度综合埃默里大学 ACE U19 科学计划由以下部分组成：主要项目（Sanz，PI）：人类 SLE 协作中 B 细胞失调的机制；项目（Boss，PI）：自身免疫反应的表观遗传调控；试点项目（Ahmed，PI）： SLE 中干细胞样 CD8 T 细胞的表征预期结果将揭开疾病的谜团。发病机制；对患者进行细分；并开发生物标志物；我们的努力自然会与疾病的发生、演变和结果相吻合。 UM1 ACE 中心并为 ACE 网络的特许使命做出了巨大贡献。