Molecular Mechanisms of Integrative Signal Transduction

整合信号转导的分子机制

• 批准号: 10274862
• 负责人: Nicholas Bellono
• 金额: $ 41.01万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274862
• 关键词: Affect; Animals; Behavior; Behavioral; Biological Models; Brain; Cells; Cellular biology; Detection; Discrimination; Electrophysiology (science); Esthesia; Evolution; Fishes; Foundations; Frequencies; Hormones; Individual; Ion Channel; Methods; Molecular; Natural Products Chemistry; Octopus; Organism; Output; Partner in relationship; Physiological; Property; Proteins; Receptor Signaling; Research; Sensory; Sensory Receptors; Sentinel; Shark; Signal Transduction; Skates; Specific qualifier value; Stimulus; System; Taste Perception; Therapeutic; Tissues; Touch sensation; arm; base; bioelectricity; cell type; electric field; electrical property; expression cloning; flexibility; genetic profiling; in vivo; insight; multimodality; protein structure function; receptor; response; sensory processing disorder

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.

摘要 我们的研究方法是识别和表征特殊细胞类型中的信号传导机制， 了解各种生理系统的机械基础。该提案利用了两个 非常适合的模型系统来询问细胞如何检测和区分不同的环境信号： 1)鲨鱼和冰鞋使用专门的技术检测和区分令人难以置信的微弱和特定的电场 电感受器细胞通过利用这个独特的模型系统，我们将询问细胞是如何通过分子调节来过滤 并在指定最显著的环境信号的细微差异中进行选择。事实上，这些鱼 区分小的生物电信号，如来自猎物或配偶的生物电信号，基于它们的生理特征。 状态此外，相关的调节激素可以调节信号检测。我们最近的研究 提供了关于电感受的分子基础的见解，并建议特定的离子通道 属性有助于如何过滤输入信号。在这里，我们将研究如何电受体蛋白和 细胞特性受生理状态调节，从而影响细胞信号转导。我们将使用基因 分析、电生理学和表达克隆方法来探测病毒诱导的细胞信号传导 级联及其对细胞电调谐的贡献。然后，我们将利用这些定义的信令 级联询问是否在体内调制细胞调谐决定频率选择性的行为 动物这种方法将揭示如何整合细胞调谐有助于信号的歧视。 2)在第二个项目中，我们将探测章鱼手臂中的信号过滤机制，这些手臂被用作灵活的 这些哨兵使这些动物能够通过独特的接触在远处探索周围的环境， “触摸味觉”化学感觉的依赖形式。此外，章鱼的手臂能够处理这种 多模式的感觉信息，独立于中央大脑，产生复杂的行为。我们 研究将使用单细胞遗传分析，生理，蛋白质结构-功能和天然产物 化学方法来识别感觉受体及其特性，信号转导级联， 由手臂内的专门细胞使用的促进感觉的内在电特性。然后我们将 独立或同时激活这些受体和信号级联， 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细胞如何检测和识别多种刺激作为不同的细胞输出， 控制着生物体的功能。 这些综合性研究跨越多种专门的细胞类型，组织和生物体，以增加我们的免疫力。 了解信号转导的基础细胞生物学。