Genetic mechanisms of signal integration in the nutrient sensing network

项目摘要 真核生物已经进化出复杂的信号网络，可以评估内部能量和营养储存， 对可利用的养分作出反应。在人类中，不准确的营养感测可导致II型糖尿病， 肥胖不幸的是，可用于治疗这些疾病的治疗靶点有限。癌症进展 是由代谢的变化促进的，因为肿瘤的快速生长是由碳的失调介导的， 氮和磷的利用。一个关键的知识差距是理解真核细胞如何区分 并整合来自不同养分传感途径的信号。填补这一空白可能 确定未来糖尿病、肥胖症或癌症治疗的靶点。许多营养传感途径被用作 人类的治疗靶点最初是在真核微生物中鉴定的。然而，这项工作的大部分 集中在模式酵母酿酒酵母，它具有有限的营养利用库。 利用更多样化的营养物的真核微生物利用营养物的额外机制。 在人类中保存的感知。为了表征新的保守的营养传感调节机制， 该项目的重点是通过研究整合信号的基因来定义营养传感网络 途径和区分具有独特表型输出的真核微生物中的营养源。在 丝状真菌粗糙脉孢菌（Neurospora crassa）对可利用的营养物质的反应， 分泌的酶具有容易测量的活性。酵母Rhodosporidium toruloides 当碳丰富而氮或磷酸盐限制时，脂质积累。为了研究信号是如何 网络的整合，本项目将使用这两个非典型模式真菌容易评分的表型 关注两个问题：（1）营养感测之间信号整合的机制 途径和p38丝裂原活化蛋白激酶途径，其调节营养利用和 压力，以实现对不同刺激的下游反应;和（2）遗传机制， 整合来自碳、氮和磷酸途径信号。许多保守的途径， 人类的营养利用在真菌中起着重要作用，特别是当细胞必须区分 优选的和非优选的营养素。该项目将描述保守基因，包括三个高度保守的基因。 保守激酶，在区分真核微生物中的可用营养物中发挥作用。一个 该项目的创新之处在于使用了强大的基因组学工具，包括高通量功能基因组学 和多组学，在未充分研究的真核微生物模式生物中， 保留曲目在这两种远亲生物中工作将确定可能是 对于整个真核生物物种的营养感测是重要的，并作为治疗代谢的新靶点。 人类的疾病。相反，特定于一个物种的调节机制可以作为治疗机制。 减少真菌病死亡的目标。

PROJECT SUMMARY Eukaryotes have evolved complex signaling networks that assess internal energy and nutrient stores and respond to the available nutrients. In humans, inaccurate nutrient sensing can result in type II diabetes and obesity. Unfortunately, the therapeutic targets available to treat these diseases are limited. Cancer progression is promoted by changes in metabolism, since rapid growth of tumors is mediated by dysregulation of carbon, nitrogen, and phosphate utilization. A key knowledge gap is understanding how eukaryotic cells distinguish between available nutrients and integrate signals from diverse nutrient sensing pathways. Filling this gap may identify targets for future diabetes, obesity, or cancer therapeutics. Many nutrient sensing pathways used as therapeutic targets in humans were originally identified in eukaryotic microbes. However, much of this work focused on the model yeast Saccharomyces cerevisiae, which has a limited nutrient utilization repertoire. Eukaryotic microbes that utilize a more diverse set of nutrients employ additional mechanisms of nutrient sensing conserved in humans. To characterize novel conserved nutrient sensing regulatory mechanisms, this project focuses on defining the nutrient sensing network by investigating genes that integrate signaling pathways and distinguish between nutrient sources in eukaryotic microbes with unique phenotypic outputs. In response to available nutrients, the filamentous fungus Neurospora crassa exquisitely tailors the regulation of secreted enzymes with easily measurable activity. The oleaginous yeast Rhodosporidium toruloides accumulates lipids when carbon is abundant and nitrogen or phosphate limiting. To investigate how signaling networks are integrated, this project will use the easily scorable phenotypes of these two atypical model fungi to focus on two questions: (1) the mechanism by which signals are integrated between nutrient sensing pathways and the p38 mitogen activated protein kinase pathway, which regulates both nutrient utilization and stress, to achieve downstream responses specific to differing stimuli; and (2) the genetic mechanisms that integrate signals from carbon, nitrogen, and phosphate pathways. Many conserved pathways that regulate nutrient utilization in humans play an important role in fungi, especially when cells must distinguish between preferred and nonpreferred nutrients. This project will characterize conserved genes, including three highly conserved kinases, that play a role in distinguishing between available nutrients in eukaryotic microbes. An innovative aspect of this project is using powerful genomic tools, including high-throughput functional genomics and multi-omics, in understudied eukaryotic microbe model organisms with substantial nutrient utilization repertoires. Working in these two distantly related organisms will identify conserved genes that may be important for nutrient sensing throughout eukaryotic species and serve as novel targets to treat metabolic diseases in humans. Conversely, regulatory mechanisms specific to one species may serve as therapeutic targets to mitigate deaths from fungal disease.