Combinatorial approaches for studying multiple cues regulating human pluripotent

研究调节人类多能性的多种线索的组合方法

• 批准号: 7848757
• 负责人: Kibum Lee
• 金额: $ 231.78万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848757
• 关键词: Address; Affect; Alzheimer' s Disease; American; Biocompatible Materials; Biological Assay; Cell Lineage; Cell Therapy; Cells; Cessation of life; Cues; Degenerative Disorder; Development; Differentiation and Growth; Goals; Human; Injury; Interdisciplinary Study; Investigation; Knowledge; Life Experience; Methods; Microfluidics; Molecular; Neurons; Paralysed; Parkinson Disease; Pluripotent Stem Cells; Regenerative Medicine; Research; Resources; Signal Transduction; Small Interfering RNA; Somatic Cell; Spinal cord injury; Transfection; Transplantation; Viral; abstracting; base; combinatorial; experience; extracellular; functional genomics; genetic manipulation; innovation; insight; nanoscale; neurogenesis; novel; programs; public health relevance; relating to nervous system; self-renewal; stem cell biology; stem cell differentiation; tool

DESCRIPTION (Provided by the applicant) Abstract: Human pluripotent stem cells (hPSCs) are promising resources as cell-based therapies for the debilitating injuries caused by many neuro-degenerative diseases. However, controlling hPSC differentiation into lineage-specific neural cells is one of the most important problems needed to be addressed before their potential for neuro-regenerative medicine can be fully realized. A detailed insight into the functions of extracellular microenvironments and intrinsic cellular regulators which dynamically regulate the hPSC neurogenesis into neural/neuronal cells is a prerequisite for addressing the aforementioned challenges. However, functions of hPSC microenvironments are much more complicated to investigate because of our lack of knowledge about the multiple signals inducing differentiation and limited methods available for investigation. Therefore, the primary focus of our study is to develop innovative methods to identify optimal cues for hPSC differentiation into subtype specific neurons and genetic manipulation of hPSCs using non-viral siRNA based transfection tools. Our innovative approaches will allow for the establishment of novel cell-based assay tools and siRNA based genetic manipulation tools for selective and efficient neuro-differentiation of hPSCs. Moreover, efforts will be made to integrate these studies into one multianalytic microfluidics platform for synchronized control of microenvironmental cues and intrinsic cellular regulators synergistically. The PI's research experiences in nanoscale biomaterials, functional genomics, and stem cell biology and current interdisciplinary research programs aiming at investigating cellular interactions within microenvironments would be critical to develop the aforementioned/innovative tools. Public Health Relevance: Neuro-degenerative diseases (e.g. Alzheimer's disease and Parkinson's disease) and spinal cord injury, affects about a few million Americans, who experience life-long debilitating paralysis or even death due to the injury. Therefore, there is an urgent need for the development of cell-based therapies for neuro-regenerative medicine, where human pluripotent stem cells (hPSCs) are extremely promising resources for transplantation therapies as they possess the unique ability to self-renew and give rise to all somatic cell lineages. Goals of this proposed study is to develop innovative methods for identifying as well as understanding the temporal/spatial effects from microenvironmental cues and intrinsic cellular programs on growth, differentiation, and molecular specification of human pluripotent stem cell (hPSC) differentiation into sub-type specific neurons.

描述（由申请人提供） 摘要：人类多能干细胞（hPSC）是一种很有前途的资源，可以作为细胞疗法来治疗许多神经退行性疾病引起的衰弱性损伤。然而，在充分发挥神经再生医学潜力之前，控制 hPSC 分化为谱系特异性神经细胞是需要解决的最重要问题之一。详细了解动态调节 hPSC 神经发生为神经/神经元细胞的细胞外微环境和内在细胞调节因子的功能是解决上述挑战的先决条件。然而，由于我们缺乏对诱导分化的多种信号的了解以及可用于研究的方法有限，hPSC 微环境的功能研究起来要复杂得多。因此，我们研究的主要重点是开发创新方法，以确定 hPSC 分化为亚型特异性神经元的最佳线索，并使用基于非病毒 siRNA 的转染工具对 hPSC 进行遗传操作。我们的创新方法将允许建立新型的基于细胞的检测工具和基于 siRNA 的遗传操作工具，用于选择性和高效的 hPSC 神经分化。此外，我们将努力将这些研究整合到一个多分析微流体平台中，以协同地同步控制微环境线索和内在细胞调节剂。 PI 在纳米级生物材料、功能基因组学和干细胞生物学方面的研究经验以及当前旨在研究微环境内细胞相互作用的跨学科研究项目对于开发上述/创新工具至关重要。 公共健康相关性：神经退行性疾病（例如阿尔茨海默病和帕金森病）和脊髓损伤影响着大约数百万美国人，他们因受伤而终生瘫痪，甚至死亡。因此，迫切需要开发基于细胞的神经再生医学疗法，其中人类多能干细胞（hPSC）具有独特的自我更新和产生神经再生的能力，是移植疗法极有前途的资源。所有体细胞谱系。这项拟议研究的目标是开发创新方法，用于识别和理解微环境线索和内在细胞程序对人类多能干细胞 (hPSC) 分化为亚型特异性的生长、分化和分子规范的时间/空间影响。神经元。