Revascularization of Islets to Treat Type I Diabetes

胰岛血运重建治疗 I 型糖尿病

• 批准号: 7209702
• 负责人: ALFRED LM BOTHWELL
• 金额: $ 24.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209702
• 关键词: Address; Adult; Apoptotic; CD34 gene; Cells; Chemicals; Clinical; Clinical Trials; Collagen; Condition; Development; Diabetes Mellitus; Effectiveness; Endothelial Cells; Exposure to; Family suidae; Fetal Liver; Gel; Genes; Glucose tolerance test; Goals; Human; Immune system; Immunodeficient Mouse; Immunohistochemistry; Immunosuppressive Agents; Implant; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Islets of Langerhans Transplantation; Lead; Lymphocyte; Methodology; Microcirculatory Bed; Mus; Numbers; Organ; Organ Donor; Patients; Population; Property; Protein Overexpression; Range; Solid; Solutions; Source; Stem cells; Structure; Sus scrofa; Technology; Testing; Time; Tissues; Transplantation; Treatment Protocols; Umbilical vein; Vascular blood supply; Work; Xenograft procedure; base; blood glucose regulation; cell type; cytotoxic; immunodeficient mouse model; immunogenicity; improved; in vivo; insulin secretion; islet; model development; peripheral blood; progenitor; reconstitution; research study; success; vascular bed

DESCRIPTION (provided by applicant): A potential long term solution to type I diabetes is the transplantation of the islets of Langerhans. Notable success in recent clinical trials has been achieved with large numbers of human islets used for transplantation combined with highly developed immunosuppressive treatment protocols. The results show how effective treatment can be for a few patients but there are nowhere near adequate numbers of human islets available from donors to meet the needs of the human population. The best candidate non-human donor for islets is the pig. For islet transplantation to be optimal it is likely that improvements in their survival must be made by increasing the blood supply to the transplanted islet. Endothelial cells (EC) have been utilized to form a de novo microvascular bed in three-dimensional collagen gels. We have shown that overexpression of Bcl-2 enhances revascularization and protects human EC from destruction by cytotoxic lymphocytes. Conditions will be developed to create revascularized porcine islets or "microorgans" in these collagen gels to promote islet survival and function in vivo. Human endothelial cells and islets will be combined and their structure/function properties characterized. We will test the functionality of these grafts by performing glucose tolerance tests and insulin secretion over time. We will determine the optimum combination of human microvessels with pig islets. Proof of principle experiments will be done to show that these microorgans can cure chemically induced diabetes. It might be clinically desirable to utilize syngeneic EC from an islet microorgan recipient for the formation of microvessels. Therefore we will attempt to culture sufficient EC derived from CD34+ progenitor cells to form the microorgans. Finally, we will evaluate the immunogenicity of the microorgan grafts by reconstitution of the human immune system in immunodeficient mouse models. These studies could lead to new methodologies to treat type I diabetes enhancing both the efficiency of islet transplantation and address the severe lack of donor islets.

描述（由申请人提供）： I 型糖尿病的潜在长期解决方案是胰岛移植。最近的临床试验通过大量用于移植的人类胰岛并结合高度发达的免疫抑制治疗方案取得了显着的成功。结果表明，治疗对少数患者是多么有效，但捐赠者提供的人类胰岛数量远不足以满足人类的需求。胰岛的最佳非人类供体候选者是猪。为了使胰岛移植达到最佳效果，可能必须通过增加移植胰岛的血液供应来提高其存活率。内皮细胞（EC）已被用来在三维胶原凝胶中形成从头微血管床。我们已经证明，Bcl-2 的过度表达可增强血运重建并保护人 EC 免受细胞毒性淋巴细胞的破坏。将开发条件以在这些胶原凝胶中产生血运重建的猪胰岛或“微器官”，以促进胰岛在体内的存活和功能。人类内皮细胞和胰岛将被组合并表征它们的结构/功能特性。我们将通过进行葡萄糖耐量测试和随时间推移的胰岛素分泌来测试这些移植物的功能。我们将确定人体微血管与猪胰岛的最佳组合。将进行原理实验证明，以证明这些微生物可以治愈化学诱导的糖尿病。临床上可能需要利用来自胰岛微器官受体的同基因 EC 来形成微血管。因此，我们将尝试培养足够的源自 CD34+ 祖细胞的 EC 以形成微器官。最后，我们将通过在免疫缺陷小鼠模型中重建人类免疫系统来评估微器官移植物的免疫原性。这些研究可能会带来治疗 I 型糖尿病的新方法，提高胰岛移植的效率并解决供体胰岛严重缺乏的问题。