Validation and characterization of the caspase-6 interactome

细胞凋亡是一种基因程序化的细胞死亡过程，它利用某些称为半胱天冬酶的蛋白质，导致细胞的去除或消除，而不损害附近的其他细胞。一旦这个程序在细胞中被触发，它会导致细胞收缩，染色体和细胞器以有序的方式凝聚并形成凋亡小体，然后被相邻细胞去除。细胞凋亡在发育过程中被广泛使用，并具有适用于所有脊椎动物的广泛进化意义。在一个普通的成年人中，每天大约有500亿个细胞通过这个过程死亡。研究表明，caspase-6（一种切割某些蛋白质的分子剪刀）的激活发生在程序性细胞死亡途径的早期，并协调一系列高效的级联反应，最终导致细胞死亡和清除。当蛋白质被切割时，产生的小片段也可以参与触发和/或放大细胞的死亡。尽管大量证据表明caspase-6在细胞凋亡中的关键早期作用，但目前尚不清楚caspase-6是如何调节的以及其活化如何导致细胞死亡。Caspase-6在进化上高度保守，因此其在程序性细胞死亡中的作用对于理解真核生物的发育具有潜在的广泛意义。我的研究计划将确定哪些蛋白质调节caspase-6，以了解它是如何被激活或抑制的，并确定它切割哪些特定的蛋白质。探索凋亡细胞模型中caspase-6和其他caspase的生物学特性将为细胞凋亡/细胞死亡的基本生物学机制提供有价值的新见解，并提供对影响程序性细胞死亡途径调控的关键因素的更透彻的理解。

The role of caspase-6 in programmed cell death pathways Apoptosis, the process of a genetically programmed form of cell death that utilizes certain proteins called caspases, leads to the removal or elimination of a cell without damaging other cells in the vicinity. Once this program is triggered in the cell it causes the cell to shrink, the chromosomes and cellular organelles to condense in an orderly way and form apoptotic bodies that are then removed by neighbouring cells. Apoptosis is used extensively during development and has broad evolutionary implications applicable to all vertebrates. In an average human adult, approximately 50 billion cells die by this process per day. Research indicates activation of caspase-6, a type of molecular scissors that cleaves certain proteins, occurs early in the programmed cell death pathway and orchestrates a highly efficient series of cascades that can ultimately culminate in death and removal of a cell. When proteins are cut, the small fragments generated can also be involved in triggering and/or amplyifing the death of the cell. Despite the wealth of evidence demonstrating a critical, early role for caspase-6 in apoptosis, currently it is unclear how caspase-6 is regulated and how its activation leads to the death of the cell. Caspase-6 is highly conserved evolutionarily and thefore its role in programmed cell death has potentially wide-ranging significance towards undertanding eukaryotic development in general. My research program will identify what proteins regulate caspase-6 in order to understand how it becomes activated or suppressed, and to determine what particular proteins it cleaves. Exploring the biology of caspase-6 and other caspases in apoptotic cellular models will provide valuable new insights into the fundamental biological mechanisms underlying apoptosis/cell death as well as provide a more thorough understanding of the critical factors that influence regulation of the programmed cell death pathway.