GENETIC ANALYSIS OF MYOGENIC CELL DETERMINATION

描述（改编自研究者摘要）： 当代生物学研究的目的是确定控制 发展决策。 此外，正常的干扰 分化过程可能有助于肿瘤发生。 确定 关键的监管机制参与产生和维持 分化状态对于理解正常发育和 和疾病 本提案旨在研究细胞类型的控制 在哺乳动物细胞中的决定和分化。 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相结合的方法。 方法，肌肉调节基因的MyoD家族的调节将 被分析。 将测定型间杂种的活化和 抑制肌生成。 这种类型的遗传学研究已被用于 确定许多监管互动中的积极和消极作用 实验系统 所提出的实验利用体细胞 遗传学，以确定在横纹肌肉瘤中发现的遗传改变， 抑制肌肉分化。 与标准的分子遗传学相比， 方法，体细胞遗传学有能力确定 复杂遗传病变的功能意义，如基因 扩增，复制，倒位和易位，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，通过等染色体形成，抑制 横纹肌肉瘤的分化。 这项建议旨在 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 分化，以及确定是否存在的i（3q）s 在其他类型的肿瘤中的高频率导致类似的表型 异常

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.