Imaging the Islet Vasculature to Predict Diabetes Course

对胰岛脉管系统进行成像以预测糖尿病病程

• 批准号: 7579442
• 负责人: RICHARD JACKSON
• 金额: $ 33.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579442
• 关键词: 3-Dimensional; Adult; Affect; Alleles; Animal Disease Models; Animal Model; Antibodies; Area; Autoantibodies; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Biological Preservation; Blood Vessels; Blood Volume; C-Peptide; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Data; Detection; Development; Diabetes Mellitus; Diabetes prevention; Diagnosis; Diagnostic Procedure; Discrimination; Disease; Disease Progression; Employee Strikes; Enrollment; Evolution; Extravasation; Family history of; Figs - dietary; Flow Cytometry; Foundations; Freezing; Funding; Genetic; Genetic Markers; Genotype; Glean; Goals; Haplotypes; Histologic; Histology; Human; Image; Imagery; Imaging Techniques; Immunologic Markers; Individual; Inflammation; Inflammatory; Inflammatory Infiltrate; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Lesion; Longitudinal Studies; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Metabolic; Methods; Monitor; Morphologic artifacts; Mus; Natural History; Natural regeneration; Newly Diagnosed; Noise; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Pathogenesis; Patients; Persons; Physiologic pulse; Physiology; Pilot Projects; Population; Prediabetes syndrome; Process; Progressive Disease; Property; Protocols documentation; Research; Resolution; Risk; Sampling; Screening procedure; Sensitivity and Specificity; Series; Signal Transduction; Standardization; Subgroup; Techniques; Technology; Testing; Time; Tissue Sample; Tissues; Translating; Validation; Work; base; cellular imaging; diabetic; diabetic patient; follow-up; high risk; human subject; improved; insight; insulin secretagogues; interest; islet; nanoparticle; novel; pilot trial; programs; regenerative; research study; respiratory; response; tool; treatment effect; type I diabetic

Type 1 diabetes results from autoimmune destruction of the insulin-producing p-cells of the pancreatic islets. Understanding the pathogenic process, as well as monitoring pre-diabetic individuals or people enrolled in clinical trials, has been hampered by the inability to access the target organ and to evaluate the true status of the autoimmune lesion. During the first 4 years of this program, we developed an imaging technique to visualize the changes associated with insulitis, based on the increased vascular leakage and phagocytic activity in infiltrated islets. These features can be detected by magnetic resonance imaging (MRI), via the local accumulation .of injected paramagnetic nanoparticles (MNP) that normally remain intravascular. Experiments in animal models were followed up by a pilot trial in which the technology to image the human pancreas was improved and was applied to patients with recent-onset diabetes. The trial is still ongoing, but preliminary results show pancreatic nanoparticle accumulation in most patients, comparable with that observed in affected mice. Most suggestively, the exceptions are individuals whose genetic alleles or immune markers make them unlikely to have true autoimmune diabetes. In the proposed work, we will: 1. Completethe optimization of the clinical MR imaging technique. Although the last funding cycle saw striking improvements in the application of MNP-MRI to visualizing pancreatic inflammation in human subjects, additional enhancements await exploration. We will optimize the technique to decrease respiratory artifact, increase spatial resolution and improve quantification through changes in pulse sequences and post- processing, which might also allow reliable measures of pancreatic blood volume. We will focus on protocol standardization, in order to make the technique exportable to other MRI groups for routine use. 2. Monitor the natural history of insulitis during the development of clinical diabetes. We will perform a "natural history" study, tracking the evolution of pancreatic inflammation in at-risk individuals and in declared patients. These explorations should inform on the state of pancreatic inflammation in pre-diabetic individuals as a function of their risk status and eventual progression to diabetes. In patients with established diabetes, changes in inflammation will be correlated with rate of further p-cell loss. Aside from their mechanistic interest, these studies will lay the foundation for use in predicting disease or monitoring responses to therapy. 3. Image individuals with atypical disease features. Some diabetic patients show a very slow decline in p-cell function (LADA, individuals with very long-term C-peptide preservation). We will attempt to distinguish between a torpid inflammatory process, or an ability to vigorously regenerate p-cells, by imaging groups of such individuals. The ability to visualize and quantitate the degree of islet inflammation in diabetic or at-risk patients should provide important insights into the mechanisms that result in type 1 diabetes. It should also result in the validation of a diagnostic technique that would prove of great value in evaluating the actual risk inpre- diabetic patients, as well as the monitoring in real-time the effect of treatments in Type 1 diabetic patients.

1型糖尿病是由于胰腺中产生胰岛素的p细胞的自身免疫破坏所致。 小岛。了解发病过程，以及监测糖尿病前期患者或人 由于无法接触到目标器官并无法评估 自身免疫损伤的真实状态。在这个项目的头4年里，我们开发了一种成像 根据增加的血管渗漏和 浸润性胰岛的吞噬活性。这些特征可以通过磁共振成像(MRI)来检测， 通过注射的顺磁性纳米颗粒(MNP)的局部积累，这些纳米颗粒通常留在血管内。 在动物模型的实验之后，又进行了一项试点试验，在该试验中，对人类进行成像的技术 胰腺得到了改善，并应用于新发糖尿病患者。审判仍在进行中，但 初步结果显示，大多数患者的胰腺纳米颗粒积聚，与 在受影响的小鼠身上观察到。最具暗示意义的是，例外的是其遗传等位基因或 免疫标记物使他们不太可能患有真正的自身免疫性糖尿病。在建议的工作中，我们会： 1.完成了临床磁共振成像技术的优化。尽管上一个资金周期 MNP-MRI在显示人胰腺炎症方面的应用有了显著的进步 主题，其他增强功能有待探索。我们将优化技术以减少呼吸 伪影，提高空间分辨率，并通过脉冲序列和后处理的变化来改善量化 处理，这也可能允许可靠的测量胰腺血流量。我们将重点介绍协议 标准化，以使该技术可输出到其他MRI组进行常规使用。 2.监测临床糖尿病发展过程中胰岛素炎的自然病史。我们会 进行“自然病史”研究，追踪胰腺炎症在高危人群和 被宣布为病人。这些探查应该有助于了解糖尿病前期患者的胰腺炎症状态。 个体作为其风险状态和最终发展为糖尿病的函数。在已确定的患者中 糖尿病时，炎症的改变将与进一步的P细胞损失率相关。除了他们的 从机理上讲，这些研究将为疾病预测或监测奠定基础 对治疗的反应。 3.对具有不典型疾病特征的个体进行成像。一些糖尿病患者表现出非常缓慢的下降 在p细胞功能方面(LADA，C肽保存时间非常长的个体)。我们将尝试 通过成像区分迟钝的炎症过程，还是旺盛再生p细胞的能力 一群这样的人。 可视化和量化糖尿病或高危患者胰岛炎症程度的能力 应该对导致1型糖尿病的机制提供重要的见解。它还应该导致 一种诊断技术的验证将被证明在评估实际风险方面具有很大价值。 以及实时监测1型糖尿病患者的治疗效果。