Apoptosis regulation by RNA binding proteins

我的实验室研究细胞凋亡，一种程序性细胞死亡。它受特定基因的调控，对不同的刺激作出反应。因此，细胞凋亡是一个高度调控的事件。这种调节的一个方面发生在基因表达时，通过一个称为选择性剪接的过程。一些调节细胞凋亡的蛋白，如CASPASE 2，可选择性剪接产生促凋亡蛋白和抗凋亡蛋白。此外，负责调节这些关键细胞凋亡调节因子的蛋白质也可以经历选择性剪接，从而导致细胞凋亡调节。例如，RBM5是一种能够调节CASPASE 2选择性剪接的蛋白质，但是编码RBM5蛋白的转录物本身是选择性剪接的，具有细胞凋亡调节的功能后果。在我的实验室里，我们对RBM5和相关蛋白RBM10在调节选择性剪接和细胞凋亡中所起的作用特别感兴趣。我的研究项目旨在了解RBM5和RBM10如何调节细胞凋亡。这包括(a)更好地了解RBM5和RBM10的靶点，以及RBM5和RBM10的作用机制，以及(b)确定RBM5和RBM10表达和功能的调节因子。多年来，我们已经证明RBM5和RBM10都能够通过调节细胞因子子集的表达来影响细胞死亡。这项工作正在进行中。我们最近开始研究是什么调控RBM5和RBM10的表达。我的短期目标是专注于RBM5， RBM10及其结构变体的靶标识别。我们正在使用两个模型系统进行调查。一个是肌肉模型，另一个是肺模型。肌肉模型代表了一个正常的发育过程，包括阻止细胞增殖和促进细胞子集的死亡。肺模型代表了一种癌症系统，其中细胞凋亡总是在某种程度上被破坏，并且已知RBM5和RBM10都下调。通过这两个模型，我们希望揭示RBM5和RBM10如何在正常细胞中发挥作用，以及是什么调节了这种功能。我们研究的预期影响是，研究结果将提供关于RBM5和RBM10靶点相互作用的第一个生理学相关信息，深入了解RBM5和RBM10的表达如何被调控，以及它们的调控是否相关的信息。通过这项工作，我们希望能够更好地了解细胞凋亡的调控，特别是选择性剪接在这种调控中所起的作用。

My lab studies apoptosis, a type of programmed cell death. It is regulated by specific genes, in response to different stimuli. As a consequence, apoptosis is a highly regulated event. One aspect of this regulation occurs when genes are expressed, by a process called alternative splicing. Some proteins that regulate apoptosis, such as CASPASE 2, are alternatively splicing to produce both pro- and anti-apoptosis proteins. In addition, the proteins responsible for the regulation of these key apoptosis regulatory factors can also experience alternative splicing, with consequences for apoptosis regulation. For instance, RBM5 is a protein with the ability to regulate CASPASE 2 alternative splicing, but the transcript encoding RBM5 protein is itself alternatively spliced, with functional consequences for apoptosis regulation. In my lab, we are particularly interested in the role played by RBM5, and a related protein RBM10, in modulating both alternative splicing and apoptosis. My research program is aimed at understanding how RBM5 and RBM10 function to regulate apoptosis. This involves (a) gaining a better understanding of the targets of RBM5 and RBM10, and the RBM5 and RBM10 mechanisms of action, and (b) identifying the regulators of RBM5 and RBM10 expression and function. Over the years we have demonstrated that both RBM5 and RBM10 are able to influence cell death by regulating the expression of a subset of cellular factors. This work in ongoing. We have recently begun to investigate what regulates the expression of both RBM5 and RBM10. My short-term objective is to focus on target identification for RBM5, RBM10 and the structural variants thereof. We are carrying out our investigations using two model systems. One is a muscle model and the other is a lung model. The muscle model represents a normal developmental process that involves preventing cell multiplication and promoting death in a subset of cells. The lung model represents a cancer system, where apoptosis is always disrupted at some level, and both RBM5 and RBM10 are known to be downregulated. Using these two models we hope to shed light on how RBM5 and RBM10 function in normal cells and what regulates this function.  The anticipated impact of our study is that the results will provide the first physiologically relevant information regarding RBM5 and RBM10 target interactions, insight into how the expression of RBM5 and RBM10 are regulated, and information concerning whether or not their regulation is related. With this work, we hope to gain a better understanding of apoptosis regulation, and in particular, the role played by alternative splicing in this regulation.