ST8Sia6 modulation of diabetes

ST8Sia6 调节糖尿病

• 批准号: 10617387
• 负责人: Justin Choe
• 金额: $ 5.27万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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/10617387
• 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; Cytoplasm; Diabetes Mellitus; Diabetic mouse; Disease; Doxycycline; Engineering; Engraftment; Event; Flow Cytometry; Generations; Genetic Models; Goals; Grant; Hyperglycemia; ITIM; Iatrogenesis; Immune; Immune response; Immune system; Immunoglobulins; Immunosuppression; Immunotherapy; In Vitro; Inbred NOD Mice; Incidence; Individual; Infection; Infiltration; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Knowledge; Laboratory Finding; Lectin; Life; Ligands; Macrophage; Malignant Neoplasms; Mediator; 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; comparative; curative treatments; cytokine; diabetic; engineered beta cell; exhaust; functional status; glycemic control; immunoregulation; improved; improved outcome; innovation; insulin secretion; islet; mortality; mouse model; novel; novel strategies; overexpression; pathogen; prevent; receptor; sialic acid binding Ig-like lectin; transplant model; transplantation therapy

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.

项目摘要： 1型糖尿病会影响全球数百万个个体，这是发病率和死亡率的重要原因。 这种疾病背后的自身免疫过程尚不完全了解，使预防或治愈的尝试变得复杂 它。胰岛移植是一种潜在的治愈方法，但仍受到许多不利的阻碍 并发症，包括手术后需要的终身免疫抑制。因此，这个目的 格兰特将调查一种免疫调节方法来减轻自身免疫性，其目标是更好 了解1型糖尿病中的异常免疫反应，并有助于改善治疗 胰岛替代方法的方法。癌症和病原体已被注意到上调乙酰转移酶和 使抑制性SIGLEC受体抑制免疫排斥。实验室的先前研究发现胰岛 居民巨噬细胞表达抑制性Siglec-E受体，该受体结合由 siAlyltransferase ST8SIA6。这导致了中心假设，即在 胰岛的β细胞可以预防自身免疫排斥。为了测试这一点，我们开发了一部小说 小鼠以β细胞特异性表达ST8SIA6的非肥胖糖尿病背景，并具有 表现出强大的疾病保护。中心假设将以两个具体目标解决。这 将探索保护自发和诱发自身免疫的机械基础。免疫分析 通过流式细胞仪将有助于阐明保护自身免疫活性的细胞和分子事件。 该项目认识到免疫反应的复杂动态，并考虑了先天和 自身免疫的适应性介体研究了新的免疫调节路径。另外，潜力 这项工作的治疗应用将进行测试。我们的遗传模型包括一个四环素 - 关闭参数， 允许进行临时研究，以调查稳健的ST8SIA6表达的最低要求的时间 一旦开始，保护或ST8SIA6改变自身免疫性疾病过程的能力。我们还将雇用 新型胰岛移植模型以确定ST8SIA6表达β细胞是否可以恢复血糖 没有免疫抑制的控制。最终，这项工作将有助于提高对 自身免疫性和一种避免免疫排斥的潜在组织内部方法。