Intravital Imaging of Type I Diabetes

I 型糖尿病的活体成像

• 批准号: 8114678
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 38.55万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114678
• 关键词: Abbreviations; Abdomen; Ablation; Address; Antigens; Autoimmune Process; Autoimmunity; Bypass; CD8B1 gene; Catalytic Domain; Cells; Clinical; Cross Presentation; Data; Dendritic Cells; Developed Countries; Development; Diabetes Mellitus; Disease; Disease Progression; Electronics; Endothelial Cells; Erythrocytes; Event; Glucose-6-Phosphate; Goals; Hand; Homing; Image; Immune system; In Vitro; Inbred NOD Mice; Incidence; Individual; Infiltration; Inflammation; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Link; Methods; Microscopy; Molecular; Mus; Myotonic Dystrophy; Natural regeneration; Organ; Pancreas; Peptides; Phosphotransferases; Printing; Proteins; Protocols documentation; Rattus; Research; Research Personnel; Role; Solutions; Staging; Study Section; System; T-Lymphocyte; Techniques; Testing; Therapeutic Intervention; Time; Time Study; United States National Institutes of Health; Vascular Endothelium; autoreactive T cell; base; cell type; cyanine; in vivo; intravital microscopy; islet; movie; novel; novel strategies; postcapillary venule; programs; promoter; research study; rhodamine isothiocyanate; tetramethylrhodamine isothiocyanate; trafficking

DESCRIPTION (provided by applicant): Three major events happen in organ-specific autoimmunity during disease progression: autoreactive T cells are generated (I), they traffic to the target organ (II), and they destroy the organ (III). Type 1 diabetes (T1D) is a clear example of such a disease. Its incidence is on the rise in developed countries, and the most efficient therapy for T1D is still the provision of insulin. We have been focusing on the studies of T cell homing to the insulin-producing islets, combining in vivo and in vitro approaches for tracing T cells and searching for molecular clues to what drives T cells to the islets. The goal of these studies is to find targets for blocking homing of T cells for therapeutic intervention in T1D. We came to realization that progress in the field was hampered by the inability to follow the fate of individual islets during T cell attack. Clearly, should we have had this possibility in hand, we would progress much faster in understanding the rules of T cell infiltration, and also in following the fate of 2 cells after T cell ablation and test 2 cell regeneration protocols. To achieve these goals, we came up with a simple solution: an abdominal window allowing intravital microscopy (AWIM). We perfected the technique to the point where we can comfortably address many issues related to T cell homing and islet destruction/regeneration. We also will employ a novel whole organ imaging approach to delineate the global features of inflammation in the pancreas during T1D development. Accordingly, we will pursue the following Specific Aims. Specific Aim 1. Further delineate the role of cross-presentation in homing of T cells. Specific Aim 2. Study the homing of naturally activated T cells to the pancreas. . PUBLIC HEALTH RELEVANCE: The proposed research will take advantage of the novel approach developed in the PI's lab to visualize the events leading to destruction of insulin-producing islets by autoimmune T cells. T cell homing will be studied in real-time. The acquired knowledge will be instrumental for development of new clinical strategies for islet protection and regeneration.

描述（由申请人提供）：疾病进展过程中器官特异性自身免疫的三个重大事件发生：自动反应性T细胞（i），它们流向目标器官（II），并破坏器官（III）。 1型糖尿病（T1D）是这种疾病的明显例子。发达国家的发病率正在上升，T1D的最有效疗法仍然是胰岛素的提供。我们一直专注于对产生胰岛素产生胰岛的T细胞寄养，结合体内和体外方法，用于追踪T细胞，并寻找将T细胞驱动到胰岛的分子线索。这些研究的目的是找到阻断T细胞在T1D中进行治疗干预的目标。我们意识到该领域的进步受到了在T细胞攻击期间无法遵循单个小岛的命运的阻碍。显然，如果我们手头有这种可能性，我们将在理解T细胞浸润的规则方面以及遵循T细胞消融和测试2个细胞再生方案后的2个细胞的命运方面的进步更快。为了实现这些目标，我们提出了一个简单的解决方案：一个腹部窗口允许插入式显微镜（AWIM）。我们完善了该技术，以至于我们可以舒适地解决与T细胞归巢和胰岛破坏/再生有关的许多问题。我们还将采用一种新型的整个器官成像方法来描述T1D开发过程中胰腺炎症的全球特征。因此，我们将追求以下特定目标。具体目的1。进一步描述交叉呈现在T细胞归巢中的作用。具体目的2。研究自然活化的T细胞向胰腺寄养。 。 公共卫生相关性：拟议的研究将利用PI实验室中开发的新方法，以可视化导致自身免疫T细胞破坏胰岛素产生胰岛的事件。 T细胞归巢将进行实时研究。获得的知识将有助于制定胰岛保护和再生的新临床策略。