Controlling tissue size by noise and feedback

通过噪声和反馈控制组织尺寸

• 批准号: 9276674
• 负责人: Mary N Teruel
• 金额: $ 34.22万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276674
• 关键词: ATAC-seq; Adipocytes; Adipose tissue; Adult; Aging; Back; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Differentiation process; Cell Fraction; Cells; ChIP-seq; Chromatin; Circadian Rhythms; Computer Simulation; Defect; Diabetes Mellitus; Epidemic; Feedback; Fluorescence Microscopy; Fluorescent in Situ Hybridization; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Hematopoietic; Hormonal; Human; In Vitro; Insulin Resistance; Lipids; Mammalian Cell; Mammals; Mass Spectrum Analysis; Mediating; Medical; Messenger RNA; Microfluidics; Microscopy; Molecular; Neurons; Noise; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Outcome; PPARG gene; Pathway interactions; Pattern; Process; Proliferating; Publishing; Reporter; Signal Transduction; Stem cells; Stimulus; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Undifferentiated; Variant; Work; adipocyte differentiation; base; cell injury; cell type; cellular imaging; in vivo; insight; lipid biosynthesis; models and simulation; novel; novel strategies; precursor cell; prevent; protein expression; public health relevance; response; system architecture; tool; transcription factor

 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.

 描述（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。该提案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，或将增殖的前体细胞转化为不可分裂的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实现的实验系统之一。了解脂肪生成也具有重大的医学意义，因为脂肪生成缺陷是当前全球肥胖、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，以在蛋白质表达（噪声）方面具有足够的细胞间变异性，以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。这项工作的成果将是对可以控制小部分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 型糖尿病潜在的脂肪细胞分化缺陷的治疗干预开辟新的途径。这项研究的结果可能会产生广泛的影响 与所有细胞分化过程相关，可能有助于开发新方法来恢复有缺陷或老化的心脏、神经元、造血和其他组织。