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Engineering human islet-like organoids for transplantation

工程化人类胰岛样器官用于移植

基本信息

批准号：
10161781
负责人：
RONALD M EVANS
金额：
$ 86.5万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161781
关键词：
3-Dimensional Anatomy Anti-Inflammatory Agents Beta Cell Blood Glucose Cell Death Cell Transplantation Cell physiology Cell surface Cells Clinical Diabetes Mellitus Diabetic mouse Engineering Environment Functional disorder Generations Genetic Transcription Glucose Goals Graft Rejection Human Human Engineering Hyperglycemia Immune Immune Evasion Immune Tolerance Immune system Immunocompetent Immunodeficient Mouse Immunosuppressive Agents In Vitro Inflammation Inflammatory Inflammatory Response Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Ligands Maintenance Mesenchymal Metabolic Methods Molecular Monitor Mus NOD/SCID mouse Natural Killer Cells Organ Organoids Pharmacology Polymers Production Protocols documentation Receptor Signaling Risk Role Safety Signal Transduction Streptozocin Stress System T-Lymphocyte Techniques Teratoma Testing Therapeutic Transplantation Undifferentiated Vitamin D Vitamin D3 Receptor base cell growth cell replacement therapy clinical application cytokine diabetes mellitus therapy diabetic differentiation protocol efficacy evaluation endocrine pancreas development endoplasmic reticulum stress human pluripotent stem cell improved in vivo inhibitor/antagonist insulin secretion islet mouse model next generation novel organoid transplantation post-transplant preclinical study programmed cell death ligand 1 response stem cells systemic inflammatory response transcriptomics type I diabetic wound healing

项目摘要

ABSTRACT Pancreatic islet transplantation offers long-term treatment for Type 1 diabetes, however the shortage of donors and the need for immunosuppressive drugs restrict its therapeutic utility. Islet-like organoids generated from human pluripotent stem cells (PSCs) are an attractive alternative. Moreover, given the increasing appreciation for the role of multi-cellular organization in the functional maturation and maintenance of organs, islet-like organoids have the potential for superior functionality compared to β cells alone. The goal of this project is to develop the next generation of human islet-like organoids (HILOs) from stem cells for efficient and immune evasive transplantation. The underlying hypothesis is that a combination of a novel 3D differentiation protocol, modulation of cell surface signaling, and anti-inflammation transcriptional machinery will enable HILOs to survive long-term and function in an immune competent environment in vivo. To achieve this goal, Aim 1 proposes to establish the long-term efficacy and safety profile of HILOs, of which the function has been validated extensively in vitro. Aim 2 proposes to develop immune-tolerant HILOs by engineering the expression of PD-L1 and demonstrating the efficacy in humanized immune-competent diabetic mice. To further extend protection of transplanted HILOs, Aim 3 proposes to apply pharmacological activation of vitamin D signaling to alleviate cytokine stress on transplanted HILOs. The goal is to determine whether the incorporation of these strategies to improve survival as well as minimize allo-rejection of transplanted HILOs will result in an unlimited supply of therapeutically viable engineered islets for treating diabetes.

摘要胰岛移植为1型糖尿病提供了长期治疗，但缺乏捐赠者和对免疫抑制药物的需求限制了其治疗效果。生成类胰岛器官来自人类的多能干细胞(PSCs)是一个有吸引力的选择。此外，鉴于不断增加的赞赏多细胞组织在器官功能成熟和维持中的作用，与单独的β细胞相比，类胰岛细胞具有更好的功能潜力。这样做的目的是该项目是从干细胞中开发下一代人类胰岛样类器官(HALO)，以实现高效和免疫逃逸移植。潜在的假设是，一种新的3D区分的组合协议，细胞表面信号的调制，以及抗炎转录机制将使 HALOS能够长期存活，并在体内具有免疫能力的环境中发挥作用。为了实现这一目标，目的1建议建立HALOS的长期疗效和安全性概况，其功能已被在体外得到了广泛的验证。目的2建议通过工程表达来培育免疫耐受的HALO 并在人源化免疫功能正常的糖尿病小鼠身上展示了其疗效。为了进一步扩展移植的HALOS的保护，Aim 3建议将维生素D信号的药理激活应用于减轻移植HALOS的细胞因子应激反应。我们的目标是确定是否将这些提高存活率和最大限度减少移植的异基因排斥反应的策略将导致无限的提供治疗上可行的用于治疗糖尿病的工程胰岛。