Evolutionary conservation of caspase regulatory mechanisms

细胞凋亡是一个高度受控的过程，通过它后生动物消除不需要的和危险的细胞。细胞凋亡的失调可导致许多病症，包括癌症、自身免疫性疾病和退行性疾病。为了开发在细胞死亡未发生时促进细胞死亡或防止其不适当地发生的治疗试剂，有必要了解控制细胞凋亡的机制。到目前为止，许多重要的见解哺乳动物细胞死亡信号已告知细胞凋亡途径的研究在更简单的，实验上易于处理的模式生物。该项目将利用CI-A开发的生物化学方法和强大的基于酵母的工具，进一步探索线虫线虫的细胞死亡途径，并将其与哺乳动物细胞凋亡途径进行比较。将使用遗传学方法验证关键发现。大多数细胞凋亡刺激最终通过触发称为半胱天冬酶的蛋白酶的激活来杀死哺乳动物、昆虫或线虫细胞。然而，半胱天冬酶活性调节的机制似乎在哺乳动物和蠕虫之间有所不同。我们将解决两个一般的可能性：要么这些动物真的在细胞死亡途径的上游调控显着不同，或迄今尚未确定或充分表征的关键组件的功能对应物。了解哺乳动物细胞凋亡的调节方式将有助于设计诊断和治疗试剂，用于许多涉及细胞凋亡失调的疾病。该项目旨在确定哺乳动物和线虫之间凋亡调控的保守程度。这些知识将使研究人员能够最大限度地利用线虫细胞死亡模型，进一步阐明哺乳动物细胞死亡的调控机制，并探索如何操纵细胞凋亡以获得临床益处。

Apoptosis is a highly controlled process by which metazoans eliminate unwanted and dangerous cells. Dysregulation of apoptosis can contribute to many conditions including cancer, autoimmune and degenerative diseases. To develop therapeutic reagents that promote cell death when it fails to occur, or prevent it from happening inappropriately, it is necessary to understand the mechanisms controlling apoptosis. To date, many of the important insights into mammalian cell death signalling have been informed by studies of apoptotic pathways in simpler, experimentally tractable model organisms. This project will exploit biochemical approaches and powerful yeast-based tools developed by CI-A to further explore cell death pathways of the nematode Caenorhabditis elegans, and compare these with mammalian apoptosis pathways. Key findings will be verified using genetic approaches. Most apoptotic stimuli ultimately kill mammalian, insect or nematode cells by triggering activation of proteases termed caspases. However, the mechanisms by which caspase activity is regulated appear to differ somewhat between mammals and worms. We will address two general possibilities: either these animals really do differ significantly in the upstream regulation of cell death pathways, or that functional counterparts of key components have not hitherto been identified or fully characterised. Understanding the way in which mammalian apoptosis is regulated will aid in the design of diagnostic and therapeutic reagents for the many diseases in which dysregulation of apoptosis has been implicated. This project seeks to define the extent to which apoptotic regulation is conserved between mammals and nematodes. This knowledge will enable researchers to maximise the utility of nematode cell death models for the further elucidation of mammalian cell death regulatory mechanisms, and to explore how apoptosis can be manipulated for clinical benefit.