ST8Sia6 modulation of diabetes

ST8Sia6 调节糖尿病

基本信息

批准号：
10414792
负责人：
Justin Choe
金额：
$ 4.7万
依托单位：
MAYO CLINIC ROCHESTER
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：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414792
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Affect Allogenic Attention Autoimmune Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Binding Biological Biological Assay Biological Models Biological Response Modifiers Blood Glucose CD8-Positive T-Lymphocytes Caring Cause of Death Cell Differentiation process Cells Chronic Complex Diabetes Mellitus Diabetic mouse Disease Doxycycline Engineering Engraftment Event Flow Cytometry Generations Genetic Models Goals Grant Hyperglycemia Iatrogenesis Immune Immune response Immune system Immunoglobulins Immunosuppression Immunotherapy In Vitro Inbred NOD Mice Incidence Individual Infection Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knowledge Lectin Life Ligands Malignant Neoplasms Mediator of activation protein Modality Modeling Molecular Morbidity - disease rate Mus Non obese Onset of illness Phenotype Physiological Predisposition Procedures Process Production Replacement Therapy Role Sialic Acids Sialyltransferases Specificity System T-Lymphocyte Testing Tetracyclines Therapeutic Time Tissues Transplantation Tyrosine Work autoreactive T cell autoreactivity base comparative curative treatments cytokine diabetic engineered beta cell exhaust functional status glycemic control immunoregulation improved improved outcome innovation islet macrophage mortality mouse model novel novel strategies overexpression pathogen prevent receptor sialic acid binding Ig-like lectin transplant model transplantation therapy

项目摘要

Project summary: Type 1 diabetes affects millions of individuals globally, and is a significant cause of morbidity and mortality. The autoimmune process behind this disease is not fully understood, complicating attempts to prevent or cure it. Islet transplantation is a potentially curative approach, but remains hindered by numerous adverse complications, including lifelong immunosuppression required after the procedure. Thus, the objective of this grant is to investigate an immunomodulatory approach for mitigating autoimmunity, with the goals of better understanding the aberrant immune response in type 1 diabetes and contributing to an improved therapeutic approach for islet replacement. Cancers and pathogens have been noted to upregulate sialyltransferases and engage inhibitory Siglec receptors to dampen immune rejection. Previous studies in the lab found that islet resident macrophages express the inhibitory Siglec-E receptor, which binds sialic acid residues generated by the sialyltransferase ST8Sia6. This leads to the central hypothesis that induced ST8Sia6 expression in the beta cells of the islet can protect against autoimmune rejection. To test this, we have developed a novel mouse on the non-obese diabetic background that expresses ST8Sia6 in a beta cell specific manner, and have shown robust protection from disease. The central hypothesis will be addressed in two specific aims. The mechanistic basis of protection from spontaneous and induced autoimmunity will be explored. Immune profiling via flow cytometry will help elucidate the cellular and molecular events protecting from autoimmune activity. This project recognizes the complex dynamics of the immune response and considers both innate and adaptive mediators of autoimmunity in investigating a novel immunomodulatory path. Additionally, the potential therapeutic applications of this work will be tested. Our genetic model includes a tetracycline-off parameter, allowing for temporal studies investigating the minimum required time of ST8Sia6 expression for robust protection or the ability of ST8Sia6 to alter the autoimmune disease process once initiated. We will also employ novel islet transplantation models to determine whether ST8Sia6 expressing beta cells can restore glycemic control without immunosuppression. Ultimately, this work will contribute to improved understanding of autoimmunity and a potentially tissue-intrinsic approach to avoid immune rejection.

项目概要： 1 型糖尿病影响全球数百万人，是发病和死亡的重要原因。这种疾病背后的自身免疫过程尚未完全了解，使预防或治疗的尝试变得复杂它。胰岛移植是一种潜在的治疗方法，但仍然受到许多不利因素的阻碍并发症，包括手术后所需的终生免疫抑制。因此，本次活动的目的拨款旨在研究减轻自身免疫的免疫调节方法，目标是更好地了解 1 型糖尿病的异常免疫反应并有助于改善治疗胰岛置换的方法。人们注意到癌症和病原体会上调唾液酸转移酶，结合抑制性 Siglec 受体来抑制免疫排斥。先前的实验室研究发现，胰岛常驻巨噬细胞表达抑制性 Siglec-E 受体，该受体与由巨噬细胞产生的唾液酸残基结合唾液酸转移酶 ST8Sia6。这引出了在细胞中诱导 ST8Sia6 表达的中心假设。胰岛的β细胞可以防止自身免疫排斥。为了测试这一点，我们开发了一部小说非肥胖糖尿病背景的小鼠以 β 细胞特异性方式表达 ST8Sia6，并且具有显示出对疾病的强大保护作用。中心假设将在两个具体目标中得到解决。这将探索防止自发性和诱导性自身免疫的机制基础。免疫分析通过流式细胞术将有助于阐明免受自身免疫活动影响的细胞和分子事件。该项目认识到免疫反应的复杂动态，并考虑先天和自身免疫适应性介质在研究新的免疫调节途径中的作用。此外，潜力这项工作的治疗应用将得到测试。我们的遗传模型包括四环素关闭参数，允许进行时间研究，调查 ST8Sia6 表达所需的最短时间，以实现稳健 ST8Sia6 的保护作用或改变自身免疫性疾病过程一旦开始的能力。我们还将聘请新型胰岛移植模型以确定表达 ST8Sia6 的 β 细胞是否可以恢复血糖无需免疫抑制即可控制。最终，这项工作将有助于加深对自身免疫和潜在的组织内在方法以避免免疫排斥。