Controlling tissue size by noise and feedback

 描述（由申请人提供）：细胞分化是前体细胞响应特定的内部或外部刺激而发育成新型细胞的过程。这个建议的长期目标是了解如何控制终末细胞分化的低速率，如在体内观察到的，以在正常条件下保持组织大小。脂肪细胞分化，或增殖前体细胞转化为非分裂脂肪细胞或能够积累脂质的脂肪细胞，是研究哺乳动物细胞终末分化的最容易的实验系统之一。了解脂肪生成也具有很大的医学意义，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在全球范围内流行的基础。计算建模、定量质谱和单细胞显微镜将用于识别和理解细胞使用的系统架构和分子机制，以在调节细胞分化的小分数率同时允许受控和稳定的终末细胞分化所需的蛋白质表达（噪声）中具有足够的细胞间变异性。这项工作的结果将是一个基本的系统架构和分子机制，可以控制小分数分化率的理解，开辟了新的场所的治疗干预的缺陷脂肪细胞分化胰岛素抵抗和2型糖尿病。这项研究的结果可能会有广泛的 这些结果与所有细胞分化过程相关，并且可能有助于开发新的方法来恢复有缺陷或老化的心脏、神经元、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.