Engineering a dynamic three-dimensional in vitro platform for the investigation of human Type 1 Diabetes immunopathogenesis

设计用于研究人类 1 型糖尿病免疫发病机制的动态三维体外平台

基本信息

批准号：
10677617
负责人：
Magdalena M Samojlik
金额：
$ 4.19万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677617
关键词：
3-Dimensional Address Adhesions Affect Animals Anoikis Antigens Autoimmune Diseases Beta Cell Binding Biocompatible Materials Biological Biological Assay Biomimetics Blood Vessels C-Peptide CD8-Positive T-Lymphocytes CRISPR/Cas technology CXCL10 gene Cell Communication Cell Surface Receptors Cell model Cell physiology Cell surface Cells Cellular Structures Clinical Clinical Trials Coculture Techniques Complex Controlled Environment Cytotoxic T-Lymphocytes Data Dimensions Disease Disease Progression Distress Encapsulated Engineering Environmental Risk Factor Extracellular Matrix Family suidae Functional disorder G6PC2 gene Genes Goals Hemorrhage Homing Human Hydrogels Image Image Analysis Immune In Situ In Vitro Induction of Apoptosis Insulin Insulin-Dependent Diabetes Mellitus Intervention Invaded Investigation Islets of Langerhans Knowledge Macrophage Mediating Mediator Membrane Microfluidic Microchips Microfluidics Mus Neuropathy Nutrient Organ Ovalbumin Pancreas Pathogenesis Pathway interactions Pattern Peripheral Pharmaceutical Preparations Prevention Protocols documentation Risk Role Signal Transduction Source Stimulus System T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Therapeutic Intervention Time Translating Work blood glucose regulation cell behavior cell injury cell killing cell motility cell replacement therapy chemokine comorbidity confocal imaging cost cytokine cytotoxic CD8 T cells cytotoxicity diabetes pathogenesis endocrine pancreas development experimental study histological specimens immune activation immunopathology improved in situ imaging in vitro Model innovation insight islet microphysiology system migration mouse model prevent screening spatial integration therapy outcome tool

项目摘要

PROJECT SUMMARY/ABSTRACT Type 1 Diabetes (T1D) is an autoimmune disease caused by aberrant T-cell mediated targeted destruction of insulin-producing beta cells in the pancreas, resulting in loss of blood glucose regulation, with increased long- term risks of vascular and neuropathic comorbidities. Despite the fact that T1D is one of the most studied organ- specific autoimmune diseases, the various strategies aimed at intervention, prevention, or reversal of this disease have failed to succeed due to incomplete knowledge about the precise mechanisms of their action, as only peripheral assessments of systemic impacts (e.g., circulating cytokine changes, C-peptide levels) are feasible. This lack of mechanistic understanding of these interventions, as well as substantial time and cost of clinical trials, is a profound obstacle in improving therapeutic outcomes. To address these significant knowledge gaps, there is a substantial clinical need to develop human-based ex vivo systems capable of intimately studying the interplay of islets and immune cells, as well as the contribution of environmental factors on immune cell activation, homing, and cytotoxicity. The primary hypothesis of this proposal is that the development of an islet- immune platform has the potential to provide unique insight into T1D, with investigation of activation pathways and screening of interventional approaches. Thus, the objective of this proposal is to engineer, validate, and utilize a unique in vitro 3-D platform for the interrogation of human T1D immunopathogenesis by converging innovative cells with biomaterials, in situ imaging, and microphysiological systems (MPS). Aim 1 will seek to establish and validate this 3D biomaterial-based co-culture platform. To validate the system, a tiered approach, building from single antigen murine model cells to human T1D-antigen cells, will be employed. Once validated, Aim 2 will translate this platform to study human-centric T1D-relevant pathways and interventions. Finally, Aim 3 will seek to integrate spatial and fluidic features by translating the 3D material to an established microphysiological system (MPS) platform, which will permit the study of T cell migration from a fluidic microenvironment to the beta cell niche. Results from this proposal should provide a validated and enabling tool for the study of human T1D-relevant pathophysiology, interventions, and therapeutics. While the proposed field of application for this platform is T1D, other autoimmune diseases can benefit from this engineered benchtop platofrm, as they share homologous hallmarks of immune cell dysregulation.

项目摘要/摘要 1型糖尿病（T1D）是一种自身免疫性疾病，由异常T细胞介导的靶向破坏胰腺中产生胰岛素的β细胞导致血糖调节的损失，长期增加血管和神经性合并症的期限风险。尽管T1D是研究最多的器官之一特定的自身免疫性疾病，旨在干预，预防或逆转的各种策略由于对其行动的确切机制的不完整知识，疾病未能成功，因为仅对系统影响的外围评估（例如，循环细胞因子变化，C肽水平）是可行的。对这些干预措施的机械理解不足，以及大量的时间和成本临床试验是改善治疗结果的深刻障碍。解决这些重要知识缺口，有很大的临床需要开发能够亲密研究的人体离体系统胰岛和免疫细胞的相互作用，以及环境因素对免疫细胞的贡献激活，归巢和细胞毒性。该提议的主要假设是胰岛的发展免疫平台有可能对T1D提供独特的见解，并研究激活途径和介绍介入方法。因此，该提案的目的是设计，验证和利用独特的体外3-D平台，通过收敛来审问人T1D免疫发病具有生物材料的创新细胞，原位成像和微生物生理系统（MPS）。 AIM 1将寻求建立并验证这个基于3D生物材料的共培养平台。为了验证系统，一种分层的方法，将采用从单个抗原鼠模型细胞到人T1D抗原细胞的建设。一旦验证， AIM 2将把这个平台转换为研究以人为中心的T1D相关途径和干预措施。最后，瞄准 3将寻求通过将3D材料转换为已建立的空间和流体特征微生物生理系统（MPS）平台，该平台将允许研究T细胞从流体中迁移微环境到Beta细胞生态市场。该提案的结果应提供经过验证和有利的工具为了研究人类T1D相关的病理生理学，干预措施和治疗剂。而拟议的领域该平台的应用是T1D，其他自身免疫性疾病可以从该工程台式机中受益 Platofrm，因为它们具有免疫细胞失调的同源标志。