Core--Islet Targeting

核心——胰岛靶向

• 批准号: 7652322
• 负责人: Hans-Ewald E. Hohmeier
• 金额: $ 16.94万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7652322
• 关键词: Animal Model; Animals; Bacteriophage M13; Bacteriophages; Binding; Cells; Collaborations; Diabetes Mellitus; Failure; Funding; Gene Delivery; Human; Image; In Vitro; Islets of Langerhans; Libraries; Life; Medical center; Methodology; Methods; Microbubbles; Molecular Target; Peptides; Phage Display; Purpose; Rattus; Technology; Transcription Coactivator; Translations; Ultrasonography; Work; base; diabetes mellitus therapy; diabetic; in vivo; islet; mature animal; new technology; novel; prevent; programs; targeted delivery; therapeutic gene

Core B - Islet Targeting The purpose of this core will be to provide novel technologies for targeting of molecular cargo to pancreatic islets, both in vitro and in living animals, to all three projects in this program. The two novel technologies resident in this core were developed under the auspices of the former Project 3 of this program in the previous five-year funding cycle. The first approach involves application of ultrasound microbubble destruction (UTMD) technology for highly efficient and specific gene delivery to pancreatic islet p-cells of adult animals in vivo. The secondapproach evolved from studies in which we screened an M13 phage display library to identify peptides that bind specifically to pancreatic islet p-cells, and subsequently demonstrated that the cognate phage targets islet p-cells of adult animals in a selective fashion. We believe that these technologies will have different immediate applications to the three projects, so we propose to deploy these technologies in three activity centers: 1) At Duke, Dr. Hans Hohmeier and colleagues will work with Dr. Paul Grayburn to optimize the UTMD technology for delivery of genes to p-cells of living Zucker Diabetic fatty rats, and will then perform studies aimed at reversing or preventing p-cell failure of diabetes in these animals in close collaboration with Project 1; 2) At the Baylor Medical Center in Dallas, Dr. Grayburn and colleagues will collaborate closely with Project 3 to develop UTMD-based methods for delivery of targeted transcriptional activators to islet p-cells, in both the in vitro and in vivo settings; 3) At UT Southwestern Medical Center in Dallas, Dr. Kathlynn Brown will optimize p-cell targeting peptides for delivery of novel imaging agents to islets in both the in vitro and in vivo settings, in close collaboration with Project 2. We believe that the novel p-cell targeting methodologies resident in Core B provide the PPG team with a remarkable opportunity for rapid translation of discoveries relating to p-cell therapeutic genes (Project 1), novel imaging agents (Project 2), and targeted transcriptional activators (Project 3) to animal models of diabetes, and if proven and validated, to human diabetes therapy.

核心B-胰岛定位 该核心的目的将是提供针对分子货物的新技术 该计划中的所有三个项目，无论是体外还是活着的动物，胰岛。两个 居住在该核心中的新技术是在以前项目3的主持下开发的 该计划在前五年的资金周期中。第一种方法涉及应用 超声微泡破坏（UTMD）技术，用于高效和特定的基因递送 到体内成年动物的胰岛P细胞。第二条方法是从研究中演变的 我们筛选了M13噬菌体显示库，以识别特异性结合的肽 胰岛P细胞，随后证明了同源噬菌体目标胰岛P细胞 成人动物以选择性的方式。我们认为这些技术将有不同的立即 对三个项目的申请，因此我们建议将这些技术部署在三个活动中心： 1）在杜克大学，Hans Hohmeier博士及其同事将与Paul Grayburn博士合作，以优化 UTMD技术用于将基因传递到活Zucker糖尿病脂肪大鼠的P细胞，然后将 执行旨在逆转或预防这些动物中糖尿病的P细胞衰竭的研究 与项目1合作； 2）在达拉斯的贝勒医学中心，格雷伯恩博士及其同事 将与项目3紧密合作，以开发基于UTMD的方法以交付目标 在体外和体内设置中，转录激活剂到胰岛P细胞； 3）在UT西南部 达拉斯的医疗中心，凯瑟琳·布朗博士将优化靶向肽的P细胞靶向新颖的肽 与项目2密切合作，在体外和体内环境中将胰岛成像为胰岛。 我们认为，核心B中居住的新颖的P细胞靶向方法为PPG团队提供了 快速翻译与P细胞治疗基因有关的发现的非凡机会 （项目1），新型成像剂（项目2）和针对性的转录激活剂（项目3） 糖尿病的动物模型，如果经过证实和验证，则可以对人类糖尿病治疗。