MOLECULAR AND GENETIC CONTROL OF PROGRAMMED CELL DEATH

程序性细胞死亡的分子和基因控制

• 批准号: 6629810
• 负责人: John M Abrams
• 金额: $ 34.27万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-15 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629810
• 关键词: Drosophilidae; active sites; apoptosis; binding proteins; cysteine endopeptidases; developmental genetics; enzyme activity; gene expression; gene mutation; genetic models; genetic regulation; phenotype; polymerase chain reaction; reporter genes; site directed mutagenesis; transcription factor; Drosophilidae; active sites; apoptosis; binding proteins; cysteine endopeptidases; developmental genetics; enzyme activity; gene expression; gene mutation; genetic models; genetic regulation; phenotype; polymerase chain reaction; reporter genes; site directed mutagenesis; transcription factor

Programmed cell death (apoptosis) is a gene-directed process responsible for the widespread and deliberate elimination of cells during animal development. Aberrant regulation apoptosis is firmly established in the etiology of some human cancers and also implicated in the progression of acquired immune deficiency syndrome (AIDS), neurodegenerative disorders and aging. The cytological features of apoptotic cell deaths are strikingly similar in all metazoans and several lines of evidence suggest that central molecular components required for this process may be highly conserved. The long-term goal of our research is to understand the molecular physiology of programmed cell death during the course of normal development. Our previous work has led to the identification of a complex genomic interval required for all naturally-occurring cell deaths in the Drosophila embryo. At least two genes in this interval appear to mediate central apoptotic functions in this model system. One of these genes, reaper, restores cell death in transformation assays, is dramatically up- regulated when ectopic cell deaths are induced and may, in fact, precede the onset of apoptosis in cells that are committed to die. The reaper gene also contributes important functions during abnormal cell deaths provoked either by X-irradiation or by developmental defects. We propose experiments designed to further characterize the function and regulation of reaper. Using cell culture assays and transgenic strains we will determine whether the product of the reaper gene is sufficient to induce apoptosis. We shall also determine the precise subcellular distribution of this gene product by immunocytochemical methods and utilize reporter gene constructs to determine how the action of reaper is regulated in both normal and abnormal contexts. Finally, we also propose a novel approach that will permit us to isolate additional genes required for cell death in Drosophila. Our studies will provide fundamental insights into mechanisms that underlie apoptosis. This information, in turn, may provide novel rationales for the treatment of some human diseases and could offer valuable new targets for drugs that specifically activate or block the apoptosis pathway.

程序性细胞死亡（凋亡）是一个基因指导的过程负责 在动物期间的广泛和故意消除细胞 发展。 异常调节凋亡在 某些人类癌症的病因学，也与 获得的免疫缺陷综合征（AIDS），神经退行性疾病 和老化。 凋亡细胞死亡的细胞学特征是 所有后生动物和几条证据都非常相似 此过程所需的中央分子成分可能高度 保守。 我们研究的长期目标是了解 正常过程中编程细胞死亡的分子生理 发展。 我们以前的工作导致了复杂基因组的识别 所有自然出现的细胞死亡所需的间隔 果蝇胚胎。 在此间隔中，至少两个基因似乎介导 此模型系统中的中央凋亡功能。 这些基因之一， 收割者是恢复转化分析中细胞死亡的 当诱导异位细胞死亡时受到调节，实际上可能在 致力于死亡的细胞中细胞凋亡的发作。 收割者 基因在异常细胞死亡期间还贡献重要功能 因X-radiation或发育缺陷而引起。 我们建议 旨在进一步表征功能和调节的实验 收割者。 使用细胞培养分析和转基因菌株，我们将 确定收割机基因的产物是否足以诱导 凋亡。 我们还将确定精确的亚细胞分布 通过免疫细胞化学方法的这种基因产物并利用记者 基因构建体以确定如何在两者中调节收割者的作用 正常和异常情况。 最后，我们还提出了一种新颖的方法 这将使我们能够隔离细胞死亡所需的其他基因 果蝇。 我们的研究将提供对机制的基本见解 这是凋亡的基础。 反过来，这些信息可能会提供新颖 治疗某些人类疾病的理由，可以提供 专门激活或阻止药物的有价值的新目标 凋亡途径。