Administrative Core

在这项U19应用中，我们建议建立我们在非人类灵长类干细胞移植方面的专业知识 (辫子猕猴)，并仔细评估移植前预适应方案对艾滋病毒的影响 水库。我们的私营部门合作伙伴将开发能够修改猕猴CCR5基因座的ZFN，以及 优化将其输送到CD34[+]干细胞的方法。综合这些努力，我们将执行 使用CCR5修饰的干细胞对猕猴进行自体移植。通过这种方式，我们希望 重述著名的柏林实验，但使用自体细胞，这样这种方法就可以 适用于绝大多数没有匹配CCR5A32捐赠者的艾滋病毒感染者。在 同时，我们将开发可以直接修改前病毒序列的SHV特异性归巢内切酶 在受感染的细胞内(使前病毒不起作用)，并优化这些HES的传递方法 CD4+T细胞和CD34+干细胞。然后我们将测试这些HES清除前病毒的能力 在我们的移植研究中，使用从猕猴身上获得的PBMC和干细胞来检测感染细胞。 这是一个复杂且高度互动的项目，汇集了多个领域的专家。因此，一个强大的 行政结构是这项工作成功开展的关键。核心的目标是： SA1.使用有效的管理、财务和科学手段确保U19高效运行 审查程序。 SA2.确保U19调查人员彼此有效沟通，与更广泛的 科学和临床社区，与其他合作者，以及项目赞助商NIH。 SAS。确保U19的调查人员遵守最高的道德标准进行 他们的研究。 行政核心将协调我们U19的行政、财政和组织方面 该计划将促进科学交流，并将为每个 项目和核心。我们的综合研究计划包括FHCRC的领先科学家， 威斯康星大学、西雅图儿童基金会、希望之城和桑加莫生物科学学院。核心的行政工作人员 将在这些机构之间搭建一座桥梁。所有人都有协调行政事务的经验 合并后的程序所产生的复杂性。

In this U19 application we propose to build upon our expertise in nonhuman primate stem cell transplantation (pigtail macaques), and carefully evaluate the effects of pretransplant conditioning regimens on the HIV reservoir. Our private sector partner will develop ZFNs capable of modifying the macaque CCR5 locus, and optimize methods for their delivery to CD34[+] stem cells. Combining these efforts, we will then perform autologous transplantation in macaques using the CCR5-modfied stem cells. In this way, we hope to recapitulate the well-known Berlin experiment, but using autologous cells such that this approach could be applied to the vast majority of HIV-infected individuals who do not have matched CCR5A32 donors. At the same time, we will develop SHIV-specific homing endonucleases that can directly modify proviral sequences within infected cells (rendering the provirus nonfunctional), and optimize methods for delivery of these HEs to CD4+ T cells and to CD34+ stem cells. We will then test the ability of these HEs to purge provirus from infected cells, using PBMC and stem cells obtained from the macaques in our transplant studies. This is a complex and highly interactive program bringing together experts in multiple fields. Thus, a strong administrative structure is critical to the successful performance of this work. The aims of the core are: SA1. Ensure that the U19 functions efficiently using effective administrative, fiscal, and scientific review procedures. SA2. Ensure that the U19 investigators communicate effectively with each other, with the broader scientific and clinical communities, with other collaborators, and with the program sponsor, NIH. SAS. Ensure that investigators in the U19 adhere to the highest ethical standards in conducting their research. The Administrative Core will coordinate the administrative, fiscal and organizational aspects of our U19 program, will facilitate scientific communication, and will provide fixed support services to each of the projects and cores. Our integrated research program includes leading scientists based at the FHCRC, the UW, Seattle Children's, City of Hope, and Sangamo Biosciences. Administrative staff members in the Core will provide a bridge between these institutions. All are experienced in coordination of the administrative complexities that a combined program creates.