Mechanisms and Therapies of B7x and B7-H3 in T1D

B7x 和 B7-H3 在 T1D 中的作用机制和治疗

基本信息

批准号：
9149198
负责人：
Xingxing Zang
金额：
$ 37.58万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9149198
关键词：
Address Affect Agonist Attenuated Autoimmune Diseases B7-DC antigen Beta Cell CD28 gene CD4 Positive T Lymphocytes CD80 gene CD8B1 gene Cell physiology Cells Chimeric Proteins Clinical Cytotoxic T-Lymphocyte-Associated Protein 4 Data Development Diabetes Mellitus Diabetic mouse Disease Elements Family Foundations Genes Goals Health Hematopoietic Histamine H3 Receptors Human Immune Inbred NOD Mice Incidence Infiltration Insulin Insulin-Dependent Diabetes Mellitus Investigation Islets of Langerhans Transplantation Kinetics Knock-out Lymphocyte Lymphocyte Activation Lymphoid Malignant neoplasm of prostate Mediating Mission Mus Non obese Organ Outcome Ovary PDCD1LG1 gene Pancreas Pathway interactions Peripheral Physiological Play Proteins Public Health Publishing RNA Splicing Regulation Regulatory T-Lymphocyte Reporting Research Resistance Role Structure Structure of beta Cell of islet Surface T cell response T-Lymphocyte Testing Transgenic Mice Transgenic Organisms Translating Treatment Efficacy VTCN1 gene Work base blood glucose regulation cancer cell design diabetic diabetogenic in vivo innovation islet member mouse model new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression programs protein H(3)receptor skills therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Mechanisms and therapies of B7x and B7-H3 in T1D T cell co-stimulation and co-inhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. Therefore these pathways are very attractive therapeutic targets. In addition to the long-standing pathway of B7-1/B7-2/CD28/CTLA-4, we and others have discovered several additional members of the B7/CD28 families over the last several years, including B7h/ICOS, PD- L1(B7-H1)/PD-L2(B7-DC)/PD-1, B7-H3/receptor(s), B7x(B7-H4 or B7S1)/receptor(s), and HHLA2/TMIGD2/receptors. Type 1 diabetes (T1D) is an autoimmune disease characterized by infiltration of lymphocytes into the islets of the pancreas and then breakdown of glucose homeostasis as a result of destruction of insulin-producing β cells by T cells. The incidence of T1D has risen steadily. Little is known about the roles of B7x and B7-H3 in the regulation of T cell function in peripheral non-lymphoid organs such as the pancreas where T1D occurs. Based on our recently published work and our exciting preliminary data, we have hypothesized in this proposal that B7x and B7-H3 are coinhibitors of effector T cells in T1D and are new therapeutic targets. This hypothesis will be tested by pursuing three specific aims: 1) Specific Aim 1: Dissect the mechanisms by which B7x inhibits T1D development; 2) Specific Aim 2: Determine the physiologic roles of B7-H3 in T1D; and 3) Specific Aim 3: Assess the therapeutic efficacy in T1D by targeting the B7x and B7-H3 pathways. We have generated a number of novel tools and have assembled a multi-disciplinary team with complementary skill sets, which provides us with unique opportunities to address challenges and achieve our goals.

描述（由申请人提供）： B7x 和 B7-H3 在 T1D T 细胞共刺激和共抑制中的机制和治疗，由 B7 家族及其受体 CD28 家族产生，在调节 T 淋巴细胞活化和耐受中具有关键作用。除了长期存在的 B7-1/B7-2/CD28/CTLA-4 通路外，我们和其他人还发现了该通路的其他几个成员。过去几年的 B7/CD28 家族，包括 B7h/ICOS、PD-L1(B7-H1)/PD-L2(B7-DC)/PD-1、B7-H3/受体、B7x(B7- 1 型糖尿病 (T1D) 是一种自身免疫性疾病，其特征是淋巴细胞浸润到胰岛，然后由于 T 细胞破坏产生胰岛素的 β 细胞而破坏葡萄糖稳态。对于 B7x 和 B7-H3 的作用，人们知之甚少。根据我们最近发表的工作和令人兴奋的初步数据，我们在本提案中追求 B7x 和 T 细胞功能的调节。 B7-H3 是 T1D 效应 T 细胞的共抑制剂，并且是新的治疗靶点，将通过三个具体目标来检验这一假设：1) 具体目标 1：剖析 B7x 抑制 T1D 发展的机制；2) 具体目标 2：确定 B7-H3 在 T1D 中的生理作用；以及 3) 具体目标 3：通过靶向 B7x 和评估 T1D 的治疗效果B7-H3 途径。我们开发了许多新颖的工具，并组建了一支具有互补技能的多学科团队，这为我们提供了应对挑战和实现目标的独特机会。