Molecular Mechanisms of Integrative Signal Transduction

摘要 我们的研究方法是识别和表征特定细胞类型的信号机制，作为一种手段 了解各种生理系统的机械基础。这项提议利用了两个 独一无二的模型系统，询问细胞如何检测和区分不同的环境信号： 1)鲨鱼和溜冰鞋使用专门的技术来检测和区分极其微弱的特定电场 电感受器细胞。通过利用这个独特的模型系统，我们将研究细胞是如何通过分子调节来过滤的 并在指定最显著环境信号的细微差异中进行选择。事实上，这些鱼 区分微小的生物电信号，如来自猎物或配偶的信号，基于它们的生理 州政府。此外，相关的调节激素可以调节信号的检测。我们最近的研究表明 提供了关于电接收的分子基础的见解，并提出了特定的离子通道 属性决定了如何过滤传入信号。在这里，我们将研究电受体蛋白和 细胞特性受生理状态的调节，从而影响细胞的信号转导。我们将使用基因 探测激素诱导的细胞信号的图谱、电生理和表达克隆方法 级联及其对蜂窝电调谐的贡献。然后，我们将利用这些定义的信令 级联询问体内细胞调谐的调制是否决定行为的频率选择性 动物。这种方法将揭示综合蜂窝调谐如何有助于信号识别。 2)在第二个项目中，我们将探索章鱼手臂的信号过滤机制，这些机制被用作灵活的 允许这些动物通过使用一种独特的接触来探索周围环境的哨兵- 依赖形式的“触觉味觉”化学感觉。此外，章鱼的手臂也有能力处理这种情况 多模式感觉信息，独立于集中的大脑，产生复杂的行为。我们的 研究将使用单细胞遗传图谱、生理、蛋白质结构功能和天然产物 识别感官受体及其性质的化学方法，信号转导级联，以及 臂内特殊细胞用来促进感觉的固有电学特性。到时候我们会的 独立或同时激活这些受体和信号级联以询问单个受体如何 蛋白质整合信息以产生特定的细胞反应和生物行为。这种方法 将使我们能够确定单个细胞如何检测和转换多个刺激作为不同的细胞输出到 管理组织的功能。 这些综合性研究跨越多种专门的细胞类型、组织和生物体，以增加我们的 了解信号转导的基本细胞生物学。

Abstract Our research approach is to identify and characterize signaling mechanisms in specialized cell types as a means to understand mechanistic underpinnings of various physiological systems. This proposal leverages two uniquely-suited model systems to ask how cells detect and discriminate diverse environmental signals: 1) Sharks and skates detect and discriminate incredibly weak and specific electric fields using specialized electroreceptor cells. By exploiting this unique model system, we will ask how cells are molecularly tuned to filter and select among the subtle differences that specify the most salient environmental signals. Indeed, these fishes discriminate between small bioelectric signals, such as those from prey or mates, based on their physiological state. Furthermore, related modulatory hormones can regulate signal detection. Our recent studies have provided insight regarding the molecular basis of electroreception and suggest that specific ion channel properties contribute how incoming signals are filtered. Here, will we investigate how electroreceptor protein and cellular properties are modulated by physiological state to affect cellular signal transduction. We will use genetic profiling, electrophysiological, and expression cloning methods to probe hormone-induced cellular signaling cascades and their contribution to cellular electrical tuning. We will then leverage these defined signaling cascades to ask whether in vivo modulation of cellular tuning determines frequency selectivity in behaving animals. This approach will reveal how integrative cellular tuning contributes to signal discrimination. 2) In a second project, we will probe mechanisms of signal filtering in octopus arms, which are used as flexible sentinels that allow these animals to explore their surroundings at a distance by using a unique contact- dependent form of ‘taste by touch’ chemosensation. Furthermore, octopus arms are capable of processing this multimodal sensory information, independent of the centralized brain, to produce sophisticated behaviors. Our studies will use single-cell genetic profiling, physiological, protein structure-function, and natural product chemistry approaches to identify sensory receptors and their properties, signal transduction cascades, and intrinsic electrical properties used by specialized cells within arms that facilitate sensation. We will then independently or simultaneously activate these receptors and signaling cascades to ask how individual receptor proteins integrate information to produce specific cellular responses and organismal behaviors. This approach will allow us to determine how single cells detect and transduce multiple stimuli as distinct cellular outputs to govern organismal function. These integrative studies span multiple specialized cell types, tissues, and organisms to increase our understanding of the basic cell biology underlying signal transduction.