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How the endocytic network mediates specificity of cell signaling

内吞网络如何介导细胞信号传导的特异性

基本信息

批准号：
10623603
负责人：
Yan Yu
金额：
$ 51.09万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2028-08-31
项目状态：
未结题

项目摘要

Abstract: How the endocytic network mediates specificity of cell signaling Receptor crosstalk – the cooperation between two or more receptors to modulate cell responses – is a key signaling mechanism. It enables cells to generate a large combinatorial repertoire of specific signaling with a limited variety of receptors. Receptor crosstalk plays an essential role in cell physiology. Consequently, dysfunctions in receptor crosstalk are associated with many human diseases, such as infectious diseases (including COVID-19), cancer, and cardiovascular diseases. To understand the physical mechanisms by which signals from different receptors are integrated in crosstalk, studies have exclusively focused on receptor interactions at the plasma membrane. In contrast, how the crosstalk signals are transduced with high fidelity from the plasma membrane to the nucleus is poorly understood and scarcely explored. The overall goal of this research is to establish the functional role of the endocytic network in transducing and regulating receptor crosstalk. Under the prior ESI-R35 support, our group has made pioneering discoveries in support of the central hypothesis that the endocytic network is where extracellular chemical and physical stimuli intertwine to regulate receptor crosstalk. Specifically, we reported a new model in which receptors can crosstalk by forming overlapping interfaces between discrete signaling clusters, challenging the prevailing view that receptors oligomerize to crosstalk. Importantly, such spatially organized interaction between receptors at endosomes and plasma membranes is modulated by extracellular physical cues, and directly regulates cell inflammatory responses. These prior discoveries and the plethora of new approaches we developed for studying endosome functions laid a critical and unique foundation for us to address the knowledge gap: how does the endocytic network mediate receptor crosstalk? We will address how the endocytic network orchestrates chemical cues from receptor crosstalk (Direction 1), and transduces extracellular physical cues to refine the specificity of crosstalk signaling (Direction 2). To address the first direction, we will define the physical mechanisms by which endocytic sorting, collective endosome-organelle interactions, and endosome-specific activation modulate crosstalk signaling originated from the plasma membrane. To address the second direction, we will integrate experiments with computational modeling to determine the feedback loop between the endocytic network and cell-matrix interactions that regulate receptor crosstalk. This project will establish a mechanistic and predictive understanding of how the endocytic network mediates the spatiotemporal specificity of receptor crosstalk and cell signaling in general; a topic that is poorly understood. It will also lower the technical barrier that has impeded research on this topic, by establishing novel quantitative toolsets for dissecting the dynamics and function of the endocytic network on multiple length scales. Ultimately, a better understanding of endosome functions in receptor crosstalk will facilitate the development of new therapeutic strategies for diseases, such as immune adjuvants for cancer therapies and vaccines.

翻译后摘要：内吞网络如何介导细胞信号的特异性受体串扰-两个或多个受体之间的合作，以调节细胞反应-是一个关键信号机制它使细胞能够产生大量的特异性信号组合，受体种类有限。受体串扰在细胞生理学中起着重要作用。因此，委员会认为，受体串扰的功能障碍与许多人类疾病有关，例如传染病（包括COVID-19）、癌症及心血管疾病。为了理解来自不同受体的信号被整合在串扰中，研究仅集中在受体上。在质膜上的相互作用。相反，如何以高保真度转换串扰信号从质膜到细胞核的过程知之甚少，几乎没有探索。本研究的总体目标是建立内吞网络在转导和调节细胞内信号转导中的功能作用，调节受体串扰。在先前的ESI-R35支持下，我们的团队取得了开创性的发现，支持核心假设，即内吞网络是细胞外化学物质和物理刺激干扰调节受体串扰。具体来说，我们报告了一种新模型，受体可以通过在离散的信号簇之间形成重叠的界面而串扰，挑战了普遍认为受体寡聚化形成串扰。重要的是，这种空间上有组织的相互作用，内体和质膜上的受体受细胞外物理信号的调节，调节细胞炎症反应。这些先前的发现和过多的新方法，为研究核内体功能而开发的一个关键和独特的基础，为我们解决核内体功能奠定了重要的基础。知识缺口：内吞网络如何介导受体串扰？我们将讨论如何内吞网络协调来自受体串扰的化学线索（方向1），并转导细胞外物理线索，以细化串扰信号传导的特异性（方向2）。为了解决第一个方向，我们将定义的物理机制，内吞分选，集体内体细胞器相互作用和内体特异性激活调节源自血浆的串扰信号传导膜的为了解决第二个方向，我们将结合实验与计算建模，确定内吞网络和调节受体的细胞-基质相互作用之间的反馈回路串话。这个项目将建立一个机制和预测性的理解如何内吞网络介导受体串扰和细胞信号传导的时空特异性;这是一个很难理解的话题。明白它还将通过建立新的技术平台，降低阻碍这一主题研究的技术壁垒。用于在多个长度尺度上解剖内吞网络的动力学和功能的定量工具集。最终，更好地理解受体串扰中的内体功能将促进新的疾病治疗策略，如癌症治疗和疫苗的免疫佐剂。