Generation of Synthetic Human Islet Microorgans

合成人类胰岛微器官的产生

基本信息

批准号：
7247810
负责人：
ALFRED LM BOTHWELL
金额：
$ 33.83万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-15 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7247810
关键词：
Affect Allogenic Animal Model Animals Architecture Autoimmune Process Beta Cell Biomedical Engineering CD34 gene Cell Survival Cell physiology Cells Chemistry Clinical Clinical Trials Collagen Collection Condition Data Development Diabetes Mellitus Endothelial Cells Excision Exposure to Fiber Fibronectins Gel Generations Genes Glucose Glucose tolerance test Goals Growth Factor Hepatocyte Growth Factor Human Immune Immune response Immune system Immunodeficient Mouse Immunosuppressive Agents Implant Injection of therapeutic agent Injury Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Islets of Langerhans Transplantation Laboratories Lead Lymphocyte Mediating Methodology Microcirculatory Bed Microspheres Modeling Molecular Mus Numbers Pancreas Patients Peripheral Blood Mononuclear Cell Polymers Production Property Protein Overexpression Proteins Protocols documentation Rate Research Personnel Resistance SCID Mice Structure Structure of beta Cell of islet Surface System Testing Therapeutic Therapeutic procedure Time Tissue Engineering Transplantation Vascular Endothelial Growth Factors Vascular blood supply Work base biodegradable polymer clinical application controlled release design exenatide immunodeficient mouse model implantation improved in vivo insulin secretion islet microorganism particle peripheral blood polylactic acid-polyglycolic acid copolymer preclinical study progenitor programs reconstitution research study scaffold size success vascular bed

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to bioengineer pancreatic beta cell-containing implants for treatment of diabetes. A major obstacle to successful transplantation of human islets is their decreased survival caused by damage during their collection and lack of adequate revascularization post-transplant. Conditions have been developed that support the survival and function of human islets in vivo in SCID (severe combined immunodeficient) mice. We previously established conditions for formation of a human microvascular bed derived from human endothelial cells (EC) that are cast in collagen/fibronectin gels and then implanted into SCID mice. Casting the islets together with EC effectively revascularize the islets. Indeed, our pilot data indicate that these human islet-EC microorganisms secrete human insulin into the peripheral blood of mice for periods of at least 4 months and demonstrate responsiveness to glucose in glucose tolerance tests. The first aim of this project is to characterize the structure/function properties of this microorganism, including the microvessel structure and the stability of the microvessels with time. Since the secretion of human insulin improves over time, we will test for proliferation of beta cells and also examine whether these microorganism can cure chemically-induced diabetes in mice. In the second aim, we will test the function of the revascularized islets when they are exposed to alloreactive human cells. Bcl-2 overexpression renders human EC resistant to allorejection. We hypothesize that the islets revascularized with Bcl-2-transduced EC will not be affected by the allogeneic human lymphocytes. For clinical use it will be necessary to develop a larger microorgan implant and optimize conditions for both survivals of beta cell function and revascularization. The third aim will utilize various synthetic molecular scaffolds to increase the size and function. Finally, the use of microspheres will be optimized for the delivery of factors that will promote beta cell survival and function. This model will have significant implications for improving post-transplant survival of human islets.

描述（由申请人提供）：该提案的总体目标是生物工程胰腺细胞的植入物来治疗糖尿病。成功移植人类胰岛的一个主要障碍是它们在收集过程中损害损害以及移植后缺乏足够的血运重建造成的生存率下降。已经开发了支持人类胰岛在体内的生存和功能的条件（严重的合并免疫缺陷型）小鼠。我们先前确定了形成源自人内皮细胞（EC）的人类微血管床的条件，这些床呈胶原蛋白/纤连蛋白凝胶，然后植入SCID小鼠。将胰岛施放，并有效地将胰岛血运重建。确实，我们的试点数据表明，这些人类胰岛微生物将人类胰岛素分泌到小鼠的外周血至少4个月，并在葡萄糖耐受性测试中表现出对葡萄糖的反应性。该项目的第一个目的是表征这种微生物的结构/功能特性，包括微血管结构和微血管随时间的稳定性。由于人类胰岛素的分泌会随着时间的推移而改善，因此我们将测试β细胞的增殖，还检查这些微生物是否可以治愈小鼠化学诱导的糖尿病。在第二个目标中，我们将在暴露于同种异体人类细胞时测试它们的血运胰岛的功能。 Bcl-2过表达使人类EC具有抗异源性。我们假设用Bcl-2转导的EC血运重建的胰岛不会受到同种异体人淋巴细胞的影响。为了临床使用，有必要开发更大的微型植入物，并优化β细胞功能和血运重建生存的条件。第三个目标将利用各种合成分子支架来增加大小和功能。最后，将对微球的使用进行优化，以递送将促进β细胞存活和功能的因素。该模型将对改善人类胰岛的移植后生存具有重要意义。