Immune system evasion of stem cell-derived cardiomyocytes

干细胞来源的心肌细胞的免疫系统逃避

• 批准号: 10216332
• 负责人: Jessica Garbern
• 金额: $ 16.8万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216332
• 关键词: Adult; Adverse effects; Allogenic; Autologous; Biocompatible Materials; Biology; Biomedical Engineering; CD47 gene; CRISPR/Cas technology; Cardiac Myocytes; Cell Line; Cell Surface Proteins; Cell Therapy; Cell Transplantation; Cell membrane; Cells; Cellular Membrane; Child; Childhood; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Development; Eating; Engineering; Engraftment; Erythrocyte Membrane; Ethics; Excision; Exposure to; Flow Cytometry; Foundations; Genes; Goals; Graft Rejection; HLA Antigens; Heart; Heart Transplantation; Heart failure; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunodeficient Mouse; Immunology; Immunosuppression; In Vitro; Infection; Infiltration; Injections; International; K-Series Research Career Programs; Lead; Macrophage Activation; Major Histocompatibility Complex; Malignant Neoplasms; Medicine; Membrane; Membrane Fusion; Membrane Proteins; Mentors; Mentorship; Methods; Modification; Molecular Biology; Mus; Myocardium; NK Cell Activation; Nanotechnology; Natural regeneration; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Physiology; Population; Pregnancy; Proteins; RNA Interference; RNA delivery; Regenerative capacity; Research; Research Personnel; Risk; Scientist; Signal Transduction; Source; Structure; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Tail; Technology; Testing; Tissue Engineering; Tissues; Training; Transplantation; United States; Universities; Veins; Work; cardiac regeneration; career; career development; congenital heart disorder; design; experience; experimental study; heart damage; human embryonic stem cell; humanized mouse; immune activation; immunocytochemistry; immunoregulation; in vivo; induced pluripotent stem cell; inherited cardiomyopathy; kidney dysfunction; macrophage; mouse model; nanoparticle; pediatric heart failure; prevent; professor; protein complex; regenerative biology; research and development; skills; small molecule; stem cell biology; stem cells; transcriptome sequencing; ventricular assist device

PROJECT SUMMARY/ABSTRACT This Mentored Clinical Scientist Research Career Development Award proposal describes a five-year research and career development training plan for Dr. Jessica Garbern to establish an independent research career in cardiac regeneration. Dr. Garbern aims to become a physician-scientist developing cellular therapies to regenerate and restore damaged cardiac tissue to treat pediatric heart failure and congenital heart disease. Dr. Garbern will be primarily mentored by Dr. Richard Lee, Professor in the Department of Stem Cell and Regenerative Biology at Harvard University, internationally recognized for his work studying heart regeneration, and co-mentored by Dr. David Mooney, Professor of Bioengineering at Harvard University, internationally recognized for his work in tissue engineering. Through the research plan, didactic experiences, and structured mentorship described in this proposal, Dr. Garbern will combine her prior background in biomaterials, molecular biology, and physiology with new skills in gene editing of induced pluripotent stem cells (iPSCs), immunology, and nanotechnology to test whether strategies to alter expression of human leukocyte antigens (HLA) will render iPSC-derived CMs hypoimmunogenic. The adult mammalian heart has a very limited ability to regenerate, and multiple strategies have been proposed to develop cell-based therapies for heart failure. To be clinically viable, such strategies must overcome barriers produced by the immune system to promote regeneration and prevent rejection of transplanted cells while avoiding the complications of chronic immunosuppression seen following heart transplant. Allogeneic CMs derived from iPSCs capable of evading the host immune system could potentially eliminate the need for immunosuppression while also be available for immediate use. Human leukocyte antigens (HLA) are cell surface proteins that allow the body to recognize foreign cells. Removal of selected HLA proteins on iPSCs that are then differentiated into CMs may prevent immune rejection of transplanted cells. In Specific Aim 1, Dr. Garbern will test the hypothesis that CMs derived from HLA-deficient iPSCs avoid T cell activation and immune rejection in vitro and in vivo. Removal of selected HLA proteins from iPSCs will be performed using CRISPR gene editing technology. Alternatively, immunomodulatory biomaterials designed to suppress the host immune response might minimize the need for immunosuppression after cell transplantation. In Specific Aim 2, Dr. Garbern will test the hypothesis that bioengineered nanoparticles capable of delivery of RNA interference to selected HLA genes will inhibit T cell activation in vitro. Through the career development activities described in this proposal, Dr. Garbern will build upon her foundations in engineering, biology and medicine to become a leader in overcoming immune barriers to transplantation of iPSC-derived CMs.

项目总结/摘要 这个指导临床科学家研究职业发展奖的建议描述了一个为期五年的研究 和职业发展培训计划杰西卡Garbern博士建立一个独立的研究生涯， 心脏再生Garbern博士的目标是成为一名医生科学家，开发细胞疗法， 再生和恢复受损的心脏组织，以治疗小儿心力衰竭和先天性心脏病。博士 Garbern将主要由干细胞系教授Richard Lee博士指导， 哈佛大学的再生生物学，因其研究心脏的工作而获得国际认可 再生，并由哈佛大学生物工程教授大卫穆尼博士共同指导， 因其在组织工程学方面的工作而获得国际认可。通过研究计划，教学经验， 和结构化的指导，加伯恩博士将联合收割机结合她以前的背景， 生物材料、分子生物学和生理学，以及诱导多能干细胞基因编辑的新技能 （iPSCs），免疫学和纳米技术，以测试改变人类白细胞表达的策略是否 抗原（HLA）将使iPSC衍生的CM低免疫原性。成年哺乳动物的心脏 有限的再生能力，并且已经提出了多种策略来开发基于细胞的疗法， 心衰为了在临床上可行，这些策略必须克服免疫系统产生的障碍 促进再生和防止移植细胞的排斥反应，同时避免慢性并发症 心脏移植后出现免疫抑制。来源于能够逃避免疫缺陷的iPSC的同种异体CM 宿主的免疫系统可以潜在地消除对免疫抑制的需要， 立即使用。人类白细胞抗原（HLA）是细胞表面蛋白，允许身体识别 外来细胞去除iPSC上的选定HLA蛋白，然后分化成CM， 移植细胞的免疫排斥。在具体目标1中，Garbern博士将测试CM来源于 来自HLA缺陷型iPSC的细胞在体外和体内避免了T细胞活化和免疫排斥。去除所选择的 来自iPSC的HLA蛋白将使用CRISPR基因编辑技术进行。可选择地， 设计用于抑制宿主免疫反应的免疫调节生物材料可以最大限度地减少对 细胞移植后的免疫抑制。在具体目标2中，Garbern博士将测试以下假设： 能够将RNA干扰递送至所选HLA基因的生物工程纳米颗粒将抑制T细胞增殖， 体外活化。通过本提案中描述的职业发展活动，Garbern博士将建立 她在工程学、生物学和医学方面的基础，成为克服免疫障碍的领导者。 iPSC衍生的CM的移植。