Regulation of CD4 T cell and HIV-1 gene expression by Sam68

人类有大约2万个基因和超过50万亿个细胞。然而，秀丽隐杆线虫有大约20000个基因和大约1000个细胞。因此，人类的复杂性不是由基因的数量决定的。相反，人类基因是高度调控的，就单个基因可以通过选择性剪接和选择性聚腺苷化等过程合成多少种不同的蛋白质而言。此外，基因是通过转录成RNA来表达以及RNA翻译成蛋白质的效率来控制的。对于RNA结合蛋白如何控制有多少不同的蛋白质，以及一个基因产生了多少特定的蛋白质，人们仍然知之甚少。这一提议将决定细胞RNA结合蛋白Sam68如何控制来自特定基因的RNA丰度，这种RNA翻译成蛋白质的效率如何，以及该基因可以制造多少种不同的蛋白质。我们将在人类CD4 T细胞中分析这一点，CD4 T细胞是保护身体免受感染的免疫系统的重要组成部分。我们将确定Sam68结合位点在RNA上的位置如何控制其调节通过选择性剪接从基因中表达哪些蛋白质的能力。我们还将分析Sam68调节的基因是否控制免疫系统的重要功能。Sam68与多种类型的癌症有关，包括乳腺癌、前列腺癌、结直肠癌、宫颈癌和肾癌，以及脆性x相关震颤/共济失调综合征（FXTAS）和脊髓性肌萎缩症（SMA）。了解Sam68如何控制基因表达也可能有助于我们了解Sam68如何调节这些疾病。艾滋病毒感染导致艾滋病，是一种全球流行病。目前，已经批准的抗病毒药物针对艾滋病毒生命周期的四个阶段。然而，艾滋病毒的耐药菌株是一个问题，并且仍然非常需要新的药物靶点。开发新型抗病毒药物的一个有希望的方法是靶向细胞蛋白。HIV只有9个基因，必须劫持数百个细胞蛋白才能复制。Sam68调节HIV基因表达，但尚不清楚它是如何起作用的。HIV感染是否会通过与Sam68的相互作用改变哪些细胞蛋白的表达，特别是在细胞和病毒必须竞争Sam68的情况下，这也是未知的。因此，我们将确定HIV如何与Sam68相互作用以控制细胞和病毒基因表达。这可能决定Sam68或HIV基因表达的其他步骤是否是潜在的药物靶点。

Humans have ~20,000 genes and over 50 trillion cells. However, the C. elegans worm has ~20,000 genes and ~1000 cells. Therefore, human complexity is not determined by the number of genes. Instead, human genes are highly regulated in terms of how many different proteins can be made from a single gene using processes such as alternative splicing and alternative polyadenylation. Also, genes are controlled in terms of when they are expressed by being transcribed into RNA and how efficiently this RNA is translated into protein. There is still little understanding of how RNA binding proteins control how many different proteins and how much of a specific protein is made from a gene. This proposal will determine how the cellular RNA binding protein Sam68 controls RNA abundance from specific genes, how efficiently this RNA is translated into protein, and how many different proteins can be made from that gene. We will analyse this in human CD4 T cells, which are an essential component of the immune system that protects the body from infections. We will determine how the location of Sam68 binding sites on an RNA controls its ability to regulate which proteins are expressed from a gene through alternative splicing. We will also analyse whether the genes that Sam68 regulates control important functions for the immune system. Sam68 is implicated in several types of cancer including breast, prostate, colorectal, cervical and renal cell carcinoma as well as the diseases fragile X-associated tremor/ataxia syndrome (FXTAS) and spinal muscular atrophy (SMA). Understanding how Sam68 controls gene expression may also help us understand how Sam68 regulates these diseases.HIV infection causes AIDS and is a worldwide pandemic. Currently, there are approved antiviral drugs targeting four steps of the HIV life cycle. However, drug resistant strains of HIV are a problem and there is still a great need for new drug targets. One promising approach to develop novel antiviral drugs is to target cellular proteins. HIV has only nine genes and must highjack hundreds of cellular proteins to replicate. Sam68 regulates HIV gene expression but it is unclear how it does so. It is also unknown if HIV infection alters which cellular proteins are expressed by interacting with Sam68, especially if the cell and virus have to compete for it. Therefore, we will determine how HIV interacts with Sam68 to control cellular and viral gene expression. This may determine if Sam68 or other steps of HIV gene expression are potential drug targets.