Genetic mechanisms of signal integration in the nutrient sensing network

项目总结 真核生物进化出复杂的信号网络，评估内部的能量和营养储存，并 对可用的营养物质做出反应。在人类中，不准确的营养感知可能会导致II型糖尿病和 肥胖。不幸的是，可用于治疗这些疾病的治疗目标有限。癌症进展 是由新陈代谢的变化推动的，因为肿瘤的快速生长是由碳调节失调所介导的， 氮和磷的利用。一个关键的知识空白是理解真核细胞如何区分 在可利用的营养素之间建立联系，并整合来自不同营养感知途径的信号。填补这一空白可能会 确定未来糖尿病、肥胖症或癌症治疗的目标。许多营养传感通路被用作 人类的治疗靶点最初是在真核微生物中确定的。然而，这些工作中的大部分 重点研究了模式酵母酿酒酵母，它的营养利用谱有限。 真核微生物利用更多样化的营养物质，使用额外的营养机制。 感觉在人类中是保守的。为了描述新的保守的营养感应调节机制，这 该项目的重点是通过研究整合信号的基因来定义营养感知网络 具有独特表型输出的真核微生物中营养来源的途径和区分。在……里面 丝状真菌粗脉孢子菌对可利用的营养物质做出反应，巧妙地调整了对 分泌酶的活性很容易测量。产油酵母菌红孢子菌 当碳充足，氮或磷有限时，脂肪就会积累起来。要调查信令如何 网络是集成的，这个项目将使用这两个非典型模式真菌容易评分的表型 将重点放在两个问题上：(1)营养传感之间信号整合的机制 途径和p38丝裂原激活的蛋白激酶途径，它调节营养利用和 应激，以实现对不同刺激的特定下游反应；以及(2) 整合来自碳、氮和磷途径的信号。许多保守的调控途径 人类对养分的利用在真菌中扮演着重要的角色，特别是当细胞必须区分 首选和非首选营养素。这个项目将描述保守的基因，包括三个高度保守的基因 保守的激酶，在区分真核微生物中可用的营养物质方面发挥了作用。一个 该项目的创新方面是使用强大的基因组工具，包括高通量功能基因组学 和多组学，在未被充分研究的真核微生物模式生物中，大量利用营养 剧目。在这两个远亲生物体中工作将识别可能是 对整个真核物种的营养感知很重要，并作为治疗代谢的新靶点 人类的疾病。相反，特定于一种物种的调节机制可能起到治疗作用。 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.