Clinically Relevant CiPS Cell Lines

描述（由申请人提供）：本提案中概述的研究旨在为研究和开发新的临床可翻译的iPS细胞系提供一个平台，特别是解决当前iPS程序的缺点，这些缺点阻碍了该方法在临床中的潜在翻译。通过体外定向重编程诱导体细胞多能状态，即诱导多能干细胞（iPS），对于疾病和患者特异性细胞系的产生以及细胞治疗具有重要的潜在意义（1,2,3）。虽然很有前途和革命性，但迄今为止，iPS技术有几个主要缺点，这些缺点共同阻碍了该方法在临床应用中的潜在转化。我们的长期目标（II期及以后）是开发能够将iPS细胞转化为临床治疗的工具和细胞系。提出的研究背后的具体假设是，改进更多临床可翻译的iPS程序，如使用iPS信号转导途径的小分子诱导剂，可以设计简化“临床可翻译”的人类iPS细胞系的开发。完成本提案中概述的具体目标将为通过临床相关方法评估人类iPS细胞系产生的可能性提供所需的基础，消除目前iPS细胞翻译到临床的障碍。在这个一期可行性论证项目中，我们计划在分子和细胞水平上进一步表征先前开发的人类化学诱导iPS （CiPSTM）细胞的“多能性”，包括在SCID小鼠模型中的研究。此外，为了准备进一步完善CiPS方法（II期），我们将使其培养和衍生适应细胞矩阵阵列（http://www.dnamicroarray.com/cell_matrix_arrays.htm）。本提案中概述的研究旨在为研究和开发新的临床可翻译诱导多能干细胞（iPS）细胞系提供一个平台，特别是解决当前iPS程序的缺点，这些缺点阻碍了该方法在临床中的潜在翻译。我们建议消除对诱导多能干细胞遗传改变的需要，提高过程的效率，并开发临床适用的诱导多能细胞鉴定方法。人类iPS细胞在产生疾病和患者特异性细胞系、细胞疗法和组织再生方面具有巨大潜力，有利于目前对可用于治疗危及生命的疾病和损伤的患者定制细胞系的未满足需求。完成本提案中概述的具体目标将为通过临床相关方法评估人类iPS细胞系产生的可能性提供所需的基础，消除目前iPS细胞系翻译到临床的障碍。

DESCRIPTION (provided by applicant): Studies outlined in this proposal are designed to provide a platform for research and development of new clinically translatable iPS cell lines specifically addressing the shortcomings of current iPS procedures that impede potential translation of this approach for use in the clinic. Induction of pluripotent status in somatic cells by directed reprogramming in-vitro, induced pluripotent stem (iPS) cells, is of great potential significance for the generation of disease and patient specific cell lines and cell therapy (1,2,3). Although quite promising and revolutionary, to date iPS techniques share several main shortcomings which collectively impede potential translation of this approach for use in the clinic. Our long-term goal (Phase II and beyond) is to develop, tools, and cell lines that allow translation of iPS cells into therapies for the clinic. The specific hypothesis behind the proposed research is that improved more clinically translatable iPS procedures such as the use of small molecule inducers of iPS signal transduction pathways, can be devised streamlining development of "clinically translatable" human iPS cell lines. Accomplishing the specific aims outlined in this proposal will provide the foundation required to assess the possibility of generation of Human iPS cell lines by clinically relevant methodologies, eliminating the current impediments for translation of iPS cells into the clinic. In this Phase I feasibility demonstration project we plan to further characterize "pluripotency" of previously developed human chemically induced iPS (CiPSTM) cells at the molecular, cellular levels including studies in SCID mouse models. Furthermore, in preparation for further refinements of the CiPS methodology (Phase II), we will adapt their cultivation and derivation to the Cell Matrix ArraysTM (http://www.dnamicroarray.com/cell_matrix_arrays.htm) PUBLIC HEALTH RELEVANCE: Studies outlined in this proposal are designed to provide a platform for research and development of new clinically translatable induced pluripotent stem (iPS) cell lines specifically addressing the shortcomings of current iPS procedures that impede potential translation of this approach for use in the clinic. We propose to eliminate the need for genetic alterations of iPS cells, increase the efficiency of the process, and develop clinically applicable identification methodologies for iPS cells. Human iPS cells hold great potential for the generation of disease and patient specific cell lines, cell therapies and tissue regeneration, benefiting the current unmet need for patient customized cell lines that could be used for treatment of life threatening diseases and injuries. Accomplishing the specific aims outlined in this proposal will provide the foundation required to assess the possibility of generation of Human iPS cell lines by clinically relevant methodologies, eliminating the current impediments for translation of iPS cell lines into the clinic.