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Improving Islet Transplantation Outcome With Akt1

使用 Akt1 改善胰岛移植结果

基本信息

批准号：
8545473
负责人：
HONGJU WU
金额：
$ 0.15万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-15 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8545473
关键词：
1-Phosphatidylinositol 3-Kinase Adenoviruses Adverse effects Apoptosis Autoimmune Process Candidate Disease Gene Capsid Cell Proliferation Cell Survival Cells Clinic Clinical Research Dose Employment Exhibits Gene Delivery Gene Expression Gene Transfer Genes Growth Factor Health Herpesvirus 1 Human Immune response Induction of Apoptosis Infection Inflammation Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Islets of Langerhans Islets of Langerhans Transplantation Knockout Mice Malignant - descriptor Malignant Neoplasms Mediating Methods Modality Modification Names Outcome Pancreas Pathway interactions Patients Process Proliferating Protein-Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Rattus Research Personnel Rodent Safety Serotyping Signal Transduction Pathway TK Gene Therapeutic Thymidine Kinase Time Toxic effect Transgenes Transgenic Mice Translating Transplantation Viral Viral Vector base clinically significant imaging modality improved in vivo interest islet mouse model promoter success suicide gene transplantation typing treatment strategy vector

项目摘要

DESCRIPTION (provided by applicant): Summary Islet transplantation is becoming a potential cure for type 1 diabetes (T1D). However, the limited supply and significant islet loss in the peritransplant period are cast as the major limitations of this treatment strategy. This project is aimed to improve the therapeutic outcome of islet transplantation by introducing constitutively active Akt1 (CA-Akt1) into the insulin producing 2-cells ex vivo. The serine/threonine protein kinase Akt/PKB is the direct downstream target of PI3 Kinase pathway, and has been found to have dual functions of anti-apoptosis and induction of cell proliferation. Relevance of Akt on 2-cell survival and proliferation has been demonstrated in studies of transgenic and knockout mouse models, as well as using pharmacological methods. Nonetheless, in order to realize the therapeutic potential of CA-Akt1, a safe, efficient and specific vector is needed to deliver Akt1 into islet 2-cells ex vivo. In this regard, adenovirus serotype 5 (Ad5)-based vector is of great interest. Our previous studies have demonstrated the modified Ad5 vector, AdRGDpK7, exhibited significantly higher gene transfer efficiency for the human islet cells. We thus propose to employ Ad5RGDpK7 to deliver Akt1 into islet cells ex vivo. To further diminish the potential adverse effect of CA-Akt1, we will restrict exogenous Akt1 expression in 2-cells by employment of 2-cell specific promoter-rat insulin promoter (RIP) to drive Akt1 expression. In addition, we propose to co-express a dual functional modality, HSV-TK, with CA-Akt1 so that it can be used as both a non-invasive imaging modality to follow the transplanted islets and a suicide gene should malignancy occur. Our specific aims are thus: 1) To develop a 2-cell specific, infectivity-enhanced Ad5 vector that allows efficient and specific CA-Akt1 and HSV-TK gene delivery into 2-cells ex vivo; 2) To examine the capacity of the Ad5 vector developed above to promote islet survival and proliferation while minimizing transformation, thus enhancing the efficacy of islet transplantation; and 3) To evaluate the safety of the Ad5 vector developed above in the context of islet transplantation.

胰岛移植正在成为治疗1型糖尿病（T1D）的潜在方法。然而，有限的供应和移植期胰岛的严重损失是这种治疗策略的主要限制。本项目旨在通过在体外将组成型活性Akt1 （CA-Akt1）引入产生胰岛素的2细胞中来改善胰岛移植的治疗效果。丝氨酸/苏氨酸蛋白激酶Akt/PKB是PI3激酶途径的直接下游靶点，具有抗凋亡和诱导细胞增殖的双重功能。Akt与2细胞存活和增殖的相关性已在转基因和敲除小鼠模型以及药理学方法的研究中得到证实。然而，为了实现CA-Akt1的治疗潜力，需要一种安全、有效和特异性的载体将Akt1体外递送到胰岛2细胞中。在这方面，基于血清5型腺病毒（Ad5）的载体引起了极大的兴趣。我们之前的研究表明，修饰后的Ad5载体AdRGDpK7对人胰岛细胞的基因转移效率显著提高。因此，我们建议使用Ad5RGDpK7将Akt1体外递送到胰岛细胞中。为了进一步减少CA-Akt1的潜在不利影响，我们将通过使用2细胞特异性启动子-大鼠胰岛素启动子（RIP）来驱动Akt1的表达，从而限制外源性Akt1在2细胞中的表达。此外，我们建议将一种双重功能模式HSV-TK与CA-Akt1共同表达，这样它既可以作为一种非侵入性的成像模式来跟踪移植的胰岛，也可以作为恶性肿瘤发生时的自杀基因。因此，我们的具体目标是：1)开发一种2细胞特异性、感染增强的Ad5载体，使CA-Akt1和HSV-TK基因能够高效、特异性地传递到2细胞体内；2)检验上述Ad5载体在促进胰岛存活和增殖的同时最小化转化的能力，从而提高胰岛移植的疗效；3)评价上述Ad5载体在胰岛移植中的安全性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regenerating β cells of the pancreas - potential developments in diabetes treatment.

DOI：
10.1080/14712598.2018.1402885
发表时间：
2018-03
期刊：
Expert opinion on biological therapy
影响因子：
4.6
作者：
Dong S;Wu H
通讯作者：
Wu H

Intra-islet glucagon-like peptide 1.

DOI：
10.1016/j.jdiacomp.2016.05.016
发表时间：
2016-11
期刊：
Journal of diabetes and its complications
影响因子：
3
作者：
Fava GE;Dong EW;Wu H
通讯作者：
Wu H

Progressive change of intra-islet GLP-1 production during diabetes development.

DOI：
10.1002/dmrr.2534
发表时间：
2014-11
期刊：
DIABETES-METABOLISM RESEARCH AND REVIEWS
影响因子：
8
作者：
O'Malley, Thomas J.;Fava, Genevieve E.;Zhang, Yanqing;Fonseca, Vivian A.;Wu, Hongju
通讯作者：
Wu, Hongju

Regulator of G protein signaling 2 is a key regulator of pancreatic β-cell mass and function.