GENETIC ANALYSIS OF MYOGENIC CELL DETERMINATION

描述(改编自调查人员摘要)：主要努力 当代生物学研究的重点是确定控制 发展决策。此外，对正常的干扰 分化过程可以促进肿瘤的发生。确定 关键监管机制参与生成和维护 分化状态对于理解两者的正常发育都很重要 和疾病。 这项建议旨在研究细胞类型的控制 哺乳动物细胞的测定和分化。通过利用成肌细胞 体外培养的细胞系以及体细胞和分子遗传学的结合 方法，肌肉调节基因MyoD家族的调节将 被分析。将检测类型间杂交种的激活和 对肌肉生成的抑制。这种类型的基因研究已经被用来 在以下几个方面确定积极和消极的监管互动 实验系统。所提出的实验利用体细胞 识别横纹肌肉瘤中发现的基因改变的遗传学 抑制肌肉分化。与标准分子遗传学相反 方法，体细胞遗传学有能力确定 基因等复杂遗传损伤的功能意义 扩增、复制、倒置和易位，发生在 肿瘤细胞。通过使用这种方法，我的实验室已经确定 ATR基因座的改变，通过等染色体的形成，抑制 横纹肌肉瘤的分化。这项提议旨在 确定ATR基因改变的分子机制 导致细胞周期异常和肌肉抑制 辨析，以及确定I(3Q)S是否在场 在其他类型的肿瘤中频率较高会导致类似的表型 异常现象。

DESCRIPTION (Adapted from investigator's abstract): A major effort in contemporary biological research is to identify genetic loci that control developmental decisions. In addition, disturbance of the normal differentiation process can contribute to tumorigenesis. Determining the key regulatory mechanisms involved in generating and maintaining the differentiated state is important for understanding both normal development and disease. This proposal is designed to investigate the control of cell type determination and differentiation in mammalian cells. By utilizing myoblast cell lines grown in vitro, and a combined somatic cell and molecular genetic approach, the regulation of the MyoD family of muscle regulatory genes will be analyzed. Intertypic hybrids will be assayed for activation and repression of myogenesis. Genetic studies of this type have been used to identify positive and negative regulatory interactions in a number of experimental systems. The experiments proposed utilize somatic cell genetics to identify genetic alterations found in rhabdomyosarcomas that inhibit muscle differentiation. In contrast to standard molecular genetic approaches, somatic cell genetics has the ability to ascertain the functional significance of complex genetic lesions, such as gene amplifications, duplications, inversions and translocations, that occur in tumor cells. By utilizing this approach, my lab has determined that alteration of the ATR locus, by isochromosome formation, inhibits differentiation in rhabdomyosarcomas. This proposal is designed to determine the molecular mechanisms by which genetic alteration of ATR results in cell-cycle abnormalities and inhibition of muscle differentiation, as well as to determine whether the i(3q)s that are present at high frequency in other types of tumor result in similar phenotypic abnormalities.