Quantitative Methods for Genome-wide Analysis of Macrophage Activation by ESCs

ESC 巨噬细胞激活的全基因组定量分析方法

• 批准号: 8244572
• 负责人: Jianqing Fan
• 金额: $ 37.5万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244572
• 关键词: Angiogenesis Inhibition; Animal Model; Biological; Cell Therapy; Classification; Computer Security; Dependence; Development; Genes; Genetic; Genomics; Human; Individual; Knowledge; Lead; Macrophage Activation; Methods; Molecular; Pathway interactions; Patients; Research; Residual state; Serum; Signal Transduction; Staging; Statistical Methods; Stem cell transplant; Stem cells; Techniques; Teratoma; Testing; Time; Transplantation; clinical application; genome wide association study; genome-wide analysis; improved; macrophage; meetings; novel; statistics; tool

DESCRIPTION (provided by applicant):The proposal intends to advance both novel statistical methods for genomic research and discoveringcomplex molecular mechanisms on the teratoma initiation and progression after transplantation ofembryonic stem cells (ESCs). The biological aims are to investigate the mechanisms and biologic pathwaysof ESC-induced macrophage activation and teratoma development; and to unveil how the human MIFpolymorphisms associated with the serum MIF concentration in order to select patients for safe celltransplantation. To meet these challenges, high-throughput genomic tools and novel statistical methods willbe combined to enhance our understanding on the macrophage function on initiation and progression ofteratomas. The research will not only focus on identifying individual gene change on macrophages, but alsoanalyze underlying biologic pathways. In addition, time-course analysis in animal models will lead to identifygenes in different transition periods from early- to late-stage of teratoma development. These biologicalstudies prompt many new challenges in statistics. In particular, novel statistical techniques are proposed toanswer the following important questions: how to improve the power of existing tests for large-scale multipletesting problems with sparsity; how to detect whether genes have expressed over time course; how to usequantitative tools for discoveries of molecular mechanisms; how to control false discovery rate undergeneral dependence; what optimal detecting boundaries of signals are under arbitrary dependence; how toestimate residual variance in ultrahigh-dimensional regression. These topics have also importantimplications on compress sensing and computer security. In addition, several robust and effective methodsare proposed for ultrahigh-dimensional sparse regression, classification, and genetic networking. Thesenewly proposed methods will be applied to genome-wide association studies to identify single-nucleotidepolymorphisms associated with MIF expression in order to select patients for safe stem cell transplantation.An important feature of the proposal is the synthesis of PIs' extensive knowledge in statistics and cellbiology to gain better understanding of complicated biological problems. PUBLIC HEALTH RELEVANCE:The teratoma formation caused by ESCs can hamper clinical applications of stem cell based therapies. Theproposed research will advance our knowledge on the initiation and progression of teratomas after ESCtransplantation and lead to effective reduction of teratoma formation by inhibition of angiogenesis viamanipulating MIF expression and targeting M2 macrophages, making stem cell transplantation safe.

描述（由申请人提供）：该提案旨在推进对基因组研究和发现在胚胎干细胞移植后畸胎瘤起始和进展的新型统计方法（ESC）。生物学的目的是研究ESC诱导的巨噬细胞激活和畸胎瘤发育的机制和生物学途径。并揭示人类的麦片肌伴形浓度与血清MIF浓度相关，以选择患者进行安全的细胞移植。为了应对这些挑战，将结合使用高通量基因组工具和新型统计方法，以增强我们对巨噬细胞功能的理解。这项研究不仅将着重于鉴定巨噬细胞的个体基因变化，而且还将识别潜在的生物学途径。此外，动物模型中的时间表分析将导致从畸胎瘤发育的早期到晚期的不同过渡期间识别基因。这些生物学研究促使统计中许多新的挑战。特别是，提出了新颖的统​​计技术，提出了以下重要问题：如何提高现有测试的大规模多层测试问题的功能；如何检测基因是否在时间过程中表达；如何使用量准的工具来发现分子机制；如何控制一般依赖的错误发现率；哪些最佳信号界限受任意依赖性；如何在超高差回归中观察残余方差。这些主题在压缩传感和计算机安全方面也具有重要的启示。此外，为超高维稀疏回归，分类和遗传网络提出了几种强大而有效的方法。该方法将应用于全基因组的关联研究，以鉴定与MIF表达相关的单核苷酸 - 多态性。 公共卫生相关性：ESC引起的畸胎瘤形成可能会阻碍基于干细胞的疗法的临床应用。培养的研究将提高我们对造成畸胎瘤的起始和进展的了解，并通过抑制血管生成的差异促进MIF表达和靶向M2巨噬细胞，从而有效地减少畸胎瘤形成，从而使干细胞移植安全。