Cell Surface Engineering for Immunoisolation in Cell Transplant Therapies

细胞移植疗法中免疫隔离的细胞表面工程

• 批准号: 8397464
• 负责人: Stephen Michael Canham
• 金额: $ 4.41万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2013-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397464
• 关键词: American; Binding; Biological; Carbohydrates; Cell Transplants; Cell membrane; Cell surface; Cells; Cellular biology; Chemicals; Chemistry; Child; Clinical; Collaborations; Complex; Cytoprotection; Development; Diagnosis; Disease; Engineering; Epitopes; Evaluation; Fellowship; Glycopeptides; Glycoproteins; Immune; Immune response; Immune system; Immunology; Inflammation; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Length; Lipid Bilayers; Membrane; Mentorship; Methods; Molecular; Molecular Biology; Molecular Structure; Mucins; Natural Killer Cells; Nature; Oligosaccharides; Operative Surgical Procedures; Peptides; Polymers; Polysaccharides; Research; Route; Structure; Surface; Training; Transplantation; Vertebral column; Work; cell injury; clinical application; clinically relevant; density; design; immunogenicity; insight; physical property; professor; response; surface coating

DESCRIPTION (provided by applicant): Over 1 million Americans are afflicted with type I diabetes and each year 13,000 additional children are diagnosed. Pancreatic islet cell transplantation has emerged as a promising treatment for type I diabetes, but its clinical application has been limited due to cellular immunogenicity. In nature, mucins are membrane-bound glycoproteins partially responsible for passivation of the immune response, but their size and complexity make their isolation and study difficult. The broad objective of this proposal is to engineer a cell surface coating that mimics the native mucins for the protection of islet cell in transplant therapy. This work will be accomplished through three Specific Aims: (1) Develop a modular synthesis of glycopeptide polymers; (2) evaluate the incorporation, molecular orientation, and internalization of the glycopeptide polymers; and (3) evaluate the glycopeptide polymers in the immunoisolation of pancreatic islet cells. Utilizing a modular synthetic approach a diversity of glycopeptide polymers will be synthesized and analyzed to correlate the relationship between chemical composition, macromolecular structure, and interaction of the glycopolymers with components of the innate immune system. These studies will provide a platform to enable an enhanced understanding of the immunology of complex mucin glycoproteins and provide the ability to study and perturb cellular recognition and immunogenicity with the intent to shield pancreatic islet cells from inflammation and damage during transplantation. PUBLIC HEALTH RELEVANCE: The research described in this application will provide a chemical approach to develop mucin mimic glycopolymers for the protection of pancreatic islet cells from eliciting an immune response during transplantation. Pancreatic islet cell transplantation has emerged as a promising therapy for the treatment of type I diabetes. The development of a modular synthetic route to mucin-like glycopolymers will permit identification of the key chemical and structural aspects responsible for biological response and permit the rational design of a mucin mimic to shield islet cells from damage and inflammation during transplantation.

描述(由申请人提供)：超过100万美国人患有I型糖尿病，每年新增13,000名儿童确诊。胰岛细胞移植是治疗I型糖尿病的一种很有前途的方法，但由于其细胞免疫原性，其临床应用受到限制。在自然界中，粘蛋白是一种膜结合的糖蛋白，部分负责免疫反应的钝化，但它们的大小和复杂性使得它们的分离和研究变得困难。这项提议的总体目标是 设计一种模仿天然粘蛋白的细胞表面涂层，在移植治疗中保护胰岛细胞。这项工作将通过三个具体目标来完成：(1)开发糖肽聚合物的模块化合成；(2)评价糖肽聚合物的掺入、分子定位和内化；以及(3)评价糖肽聚合物在胰岛细胞免疫隔离中的应用。利用模块化合成方法，将合成和分析各种糖肽聚合物，以关联化学组成、大分子结构以及糖共聚物与天然免疫系统组件之间的相互作用。这些研究将提供一个平台，使人们能够更好地了解复杂的粘蛋白糖蛋白的免疫学，并提供研究和干扰细胞识别和免疫原性的能力，目的是保护胰岛细胞在移植期间免受炎症和损害。 公共卫生相关性：本申请中描述的研究将提供一种化学方法来开发粘蛋白模拟糖共聚物，以保护胰岛细胞在移植过程中不引发免疫反应。胰岛细胞移植已成为治疗I型糖尿病的一种很有前途的治疗方法。开发一种模板式合成粘蛋白样糖共聚物的路线，将有助于识别引起生物反应的关键化学和结构方面，并允许合理设计粘蛋白模拟物，以保护胰岛细胞在移植过程中免受损伤和炎症。