Pax4-induced alpha-to-beta cell conversion

Pax4 诱导的 α 细胞向 β 细胞转化

基本信息

批准号：
9304205
负责人：
HONGJU WU
金额：
$ 33.86万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304205
关键词：
Adopted Alpha Cell Beta Cell Biological Cell Line Cell Lineage Cell Survival Cell Therapy Cell physiology Cells Clinic Clinical Trials Collaborations Data Development Diabetes Mellitus Failure Fluorescence Future Gene Transfer Genetic Glucagon Graft Survival Hormones Human Hypertrophy Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Investigation Islets of Langerhans Islets of Langerhans Transplantation Knock-in Label Letters Medical Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Pancreatectomy Patients Phenotype Proteins Public Health Replacement Therapy Reporter South Carolina Technology Therapeutic Transgenic Mice Treatment Efficacy Universities adenoviral-mediated base beta cell replacement blood glucose regulation cell type chronic pancreatitis design experimental study gene therapy improved in vivo innovation islet new therapeutic target novel pancreas development prevent research and development success therapeutic development therapeutic target transcription factor

项目摘要

SUMMARY Cell-based therapy is promising strategy for the cure of insulin deficient diabetes. One of such strategies, islet transplantation, has achieved remarkable success over the past decade, but its use is limited due to islet supply and graft survival. Another cell-based strategy is to regenerate the insulin-producing β-cells from other cell types. In the preliminary studies, we explored a strategy to regenerate β-cells from the neighboring glucagon-producing α-cells in pancreatic islets. Specifically, we explored Pax4, a transcription factor critical for the determination of α- vs β-cell lineage during development, for this purpose. Our data showed Pax4 gene transfer into αTC1.9 cells, a clonal α-cell line, induced them to adopt β-cell phenotype. We also found Pax4 gene transfer into primary human islets significantly improved β-cell function, and had circumstantial evidence indicating Pax4 not only promoted β-cell survival, but also induced α-to-β cell conversion. Despite the extensive preliminary studies, more investigations are required in order to fully realize the therapeutic potential of Pax4 and to thoroughly understand its actions. We thus propose two specific aims in this project: 1) To investigate whether Pax4 gene transfer into donor human islets improves the therapeutic efficacy of islet transplantation; and 2) To investigate whether Pax4 induces α-to-β cell conversion in primary islets and in vivo using lineage-tracing technology. Clearly, the project will provide important information regarding the therapeutic actions and potential of Pax4 for diabetes treatment.

概括基于细胞的治疗是治愈胰岛素缺乏糖尿病的承诺策略。之一在过去的十年中，这种策略，胰岛移植取得了巨大的成功，但是由于胰岛供应和移植生存，其使用受到限制。另一个基于单元的策略是再生来自其他细胞类型的产生胰岛素的β细胞。在初步研究中，我们探索了一种从相邻的产生谷歌的α细胞中再生β细胞的策略胰岛。具体而言，我们探索了PAX4，这是一种至关重要的转录因子为此，确定发育过程中α-与β细胞谱系的测定。我们的数据显示 PAX4基因转移到克隆α细胞系中的αTC1.9细胞中，诱导它们采用β细胞表型。我们还发现PAX4基因转移到原发性胰岛中可以显着改善 β细胞功能，并有间接证据表明PAX4不仅促进了β细胞生存，但还诱导α-to-β细胞转化。尽管有广泛的初步研究，但为了充分实现PAX4和彻底了解其行为。因此，我们在该项目中提出了两个具体目标：1）调查PAX4基因转移到供体胰岛中是否改善治疗胰岛移植的效率； 2）研究PAX4是否诱导α-to-β细胞使用谱系追踪技术进行主要胰岛和体内的转换。显然，项目将提供有关PAX4治疗作用和潜力的重要信息糖尿病治疗。