Controlling tissue size by noise and feedback

 描述(申请人提供)：细胞分化是前体细胞在特定的内部或外部刺激下发育成新类型细胞的过程。这项建议的长期目标是了解如何控制体内观察到的低终末细胞分化率，以维持正常条件下的组织大小。脂肪细胞分化，即将增殖的前体细胞转化为不分裂的脂肪细胞或能够积累脂肪的脂肪细胞，是研究哺乳动物细胞终末分化的最常用的实验系统之一。了解脂肪生成也有很大的医学意义，因为脂肪生成缺陷是目前肥胖、胰岛素抵抗、糖尿病和心血管疾病流行的基础。计算模型、定量质谱学和单细胞显微镜将被用来识别和理解细胞用来具有足够的细胞间蛋白质表达(噪声)的可变性的系统结构和分子机制，这是调控细胞分化的小比例比率所必需的，同时允许受控和稳定的末端细胞分化。这项工作的结果将是对可以控制小分数分化率的系统架构和分子机制的基本了解，为胰岛素抵抗和2型糖尿病相关的脂肪细胞分化缺陷的治疗干预开辟新的场所。这项研究的结果可能会有广泛的 与所有细胞分化过程相关，并可能有助于开发新的方法来修复有缺陷或老化的心脏、神经、造血和其他组织。

 DESCRIPTION (provided by applicant): Cell differentiation is a process in which a precursor cell develops into a new type of cell in response to specific internal or external stimuli. The lon term goal of this proposal is to understand how to control low rates of terminal cell differentiatin such are observed in vivo to maintain tissue size under normal conditions. Adipocyte differentiation, or the conversion of proliferating precursor cells into non-dividing fat cells or adipocytes capable of accumulating lipid, is one of the most accessible experimental systems for investigating terminal differentiation in mammalian cells. Understanding adipogenesis also has great medical relevance since defects in adipogenesis underlie the current worldwide epidemics in obesity, insulin resistance, diabetes, and cardiovascular disease. Computational modeling, quantitative mass spectrometry and single-cell microscopy will be used to identify and understand the system architecture and molecular mechanisms that cells use to have sufficient cell-to-cell variability in protein expression (noise) required to regulate small fractional rates f cell differentiation while at the same time allowing for controlled and stable terminal cell differentiation. The outcome of this work will be a fundamental understanding of the system architecture and molecular mechanisms that can control small fractional differentiation rates, opening up new venues of therapeutic intervention for the defective adipocyte differentiation underlying insulin resistance and type 2 diabetes. The results of this study will likely have broad relevance for all cell differentiation processes and may help in developing novel approaches to restore defective or aging cardiac, neuronal, hematopoietic, and other tissues.