Genetic Control of Programmed Cell Death in Drosphila

描述（由申请人提供）：果蝇细胞程序性死亡的遗传控制。 程序性细胞死亡（PCD）或细胞凋亡是一种生理过程，对正常发育和组织稳态至关重要。PCD调节的缺陷导致多种疾病的发病机制，包括与细胞死亡率降低（癌症、自身免疫）或与过度细胞死亡（神经变性、中风、心肌梗死）相关的疾病。我们研究的总体目标是全面了解多细胞生物体中PCD调控的生物学原理，识别和表征参与这一过程的基因，并开发操纵它们的方法。在这些研究中获得的知识将为与细胞凋亡率改变相关的疾病提供新的见解。 我们正在使用遗传模式生物黑腹果蝇进行这些研究。在果蝇的发育过程中，许多细胞通过PCD死亡。在脊椎动物中，这种细胞死亡不是以谱系限制的方式遗传预定的，而是取决于环境条件。因此，果蝇与脊椎动物一样具有这种发育可塑性。因此，在果蝇的分子遗传学研究承诺相当大的潜力，为推进我们的理解，在脊椎动物，包括人类的细胞凋亡的调节所涉及的基本控制机制。 在之前的资助期间，我们进行了基因筛选，旨在识别参与控制PCD的基因。我们已经鉴定了大约30个直接或间接调节细胞死亡的基因。总体目标是从表型和分子水平上表征这些基因，并揭示它们在控制PCD中的功能。我们已经揭示了细胞控制死亡和存活的新生物学原理，并将在未来继续这样做。此外，这些研究阐明了潜在的肿瘤细胞增加其对细胞凋亡的抵抗力的机制，细胞凋亡是癌症的标志。因此，这些基因的特征可能对理解人类疾病具有重要意义，并可能有助于开发治疗这些疾病的药物和疗法。

DESCRIPTION (provided by applicant): Genetic Control of Programmed Cell Death in Drosophila. Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). The overall objective of our research is to gain a comprehensive understanding of the biological principles that underlie the regulation of PCD in the context of a multi-cellular organism, to identify and characterize the genes involved in this process, and to develop methods to manipulate them. Knowledge obtained in these studies will provide new insights into diseases that are associated with altered rates of apoptosis. We are using the genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by PCD. As in vertebrates, this cell death is not genetically predetermined in a lineage-restricted manner, but is dependent on environmental circumstances. Thus, Drosophila shares this developmental plasticity with vertebrates. Therefore, molecular genetic studies in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis in vertebrates including humans. In the previous funding periods, we have performed genetic screens aimed at identifying genes involved in the control of PCD. We have identified approximately 30 genes which directly or indirectly regulate cell death. It is the overall goal to characterize these genes phenotypically and molecularly, and to reveal their function for the control of PCD. We have already revealed new biological principles by which cells control death and survival and will continue to do so in the future. Furthermore, these studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer. Therefore, the characterization of these genes may have significant implications for the understanding of human diseases, and may help developing drugs and therapies to treat these diseases.