Identification and Characterization of a Integrin - Notch signaling Axis

整合素 - Notch 信号轴的鉴定和表征

• 批准号: 8367287
• 负责人: Allan R Albig
• 金额: $ 30.25万
• 依托单位: BOISE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8367287
• 关键词: Address; Belief; Binding; Biological; Cell physiology; Cellular biology; Couples; Coupling; Data; Disease; Environment; Event; Exhibits; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Foundations; Generations; Goals; Growth; Homeostasis; Human Pathology; Individual; Integrin Binding; Integrins; Ligands; Ligation; Malignant Neoplasms; Molecular; Neoplasm Metastasis; Normal Cell; Notch Signaling Pathway; Pattern; Physiological; Porifera; Process; RGD (sequence); Regulation; Research; Research Personnel; Role; Schools; Science; Signal Transduction; Students; System; Technology; Tissues; Training; Tumor Angiogenesis; United States National Institutes of Health; angiogenesis; base; career; extracellular; genetic regulatory protein; graduate student; high school; man; notch protein; novel; programs; receptor; research study; undergraduate student

DESCRIPTION (provided by applicant): Extracellular matrix, integrins, and Notch signaling mechanism are conserved between a wide variety of multi-cellular creatures from sponges to man and under normal conditions are critical for maintaining cellular homeostasis. Conversely, under pathological conditions, extracellular matrix, integrins, and Notch signaling are collectively associated with a wide variety of human pathologies including but not limited to tumor angiogenesis, growth, invasion, and metastasis. Our preliminary results have discovered a previously unidentified signaling mechanism that couples extracellular matrix to altered Notch signaling via RGD binding ¿3 and ¿6 integrins. Therefore, the main hypothesis of this proposal is that RGD containing molecules in the extracellular matrix negatively impact Notch signaling by ligating ¿3 and ¿6 containing integrins. The main goal of this proposal is to examine this hypothesis from four different angles with four complementary specific aims. In aim 1, we will dissect the mechanistic basis by which ¿3 and ¿6 integrins suppress Notch signaling. In aim 2, we will identify ¿ integrin binding partners for ¿ and ¿6 integrins that cooperate to suppress Notch. In aim 3, we will determine if all RGD domains of pro- and anti-angiogenic extracellular matrix proteins are equally capable of suppressing Notch signaling. In aim 4, we will determine if ¿3 and ¿6 integrins suppress signaling from all Notch receptor/ligand combinations or if specific Notch receptor/ligand combinations are preferentially suppressed. By addressing these four aims, this proposal will dissect the basic parameters of a completely novel cell signaling mechanism that will have a broad impact on our understanding of normal and disease processes that as associated with extracellular matrix, integrins and Notch signaling. By addressing the basic parameters of this signaling mechanism, this proposal will lay the foundation for future research that will address the biological significance of this mechanism to cancer and angiogenesis. PUBLIC HEALTH RELEVANCE: Extracellular matrix, integrins, and Notch signaling are collectively involved in regulating an incredible diversity of events in normal and pathological cell physiology. Based on our preliminary data, we hypothesize that extracellular matrix controls Notch signaling via ¿3 and ¿6 integrins. The experiments described herein will explore this hypothesis and in so doing, will make a tremendous impact on our understanding of how extracellular matrix, integrins, and Notch signaling cooperate to control not only normal cell biology but also pathological cell biology associated with diseases such as cancer.

描述（由申请人提供）： 细胞外基质、整合素和Notch信号传导机制在从海绵到人类的多种多细胞生物之间是保守的，在正常条件下对于维持细胞稳态至关重要。相反，在病理条件下，细胞外基质、整合素和Notch信号传导与多种人类病理学共同相关，包括但不限于肿瘤血管生成、生长、侵袭和转移。我们的初步结果发现了一种先前未识别的信号传导机制，该机制通过 RGD 结合 ¿3 和 ¿6 整联蛋白将细胞外基质与改变的 Notch 信号偶联。因此，该提议的主要假设是细胞外基质中含有 RGD 的分子通过连接含有 ¿3 和 ¿6 的整联蛋白对 Notch 信号传导产生负面影响。该提案的主要目标是从四个不同的角度和四个互补的具体目标来检验这一假设。在目标 1 中，我们将剖析 ¿3 和 ¿6 整合素抑制 Notch 信号传导的机制基础。在目标 2 中，我们将鉴定 ¿ 和 ¿6 整合素的 整合素结合伴侣，共同抑制 Notch。在目标 3 中，我们将确定促血管生成细胞外基质蛋白和抗血管生成细胞外基质蛋白的所有 RGD 结构域是否同样能够抑制 Notch 信号传导。在目标 4 中，我们将确定 ¿3 和 ¿6 整合素是否抑制所有 Notch 受体/配体组合的信号传导，或者是否优先抑制特定的 Notch 受体/配体组合。通过解决这四个目标，该提案将剖析一种全新的细胞信号传导机制的基本参数，该机制将对我们对与细胞外基质、整合素和Notch信号传导相关的正常和疾病过程的理解产生广泛的影响。通过解决这种信号机制的基本参数，该提案将为未来的研究奠定基础，从而解决该机制对癌症和血管生成的生物学意义。 公共卫生相关性： 细胞外基质、整合素和 Notch 信号传导共同参与调节正常和病理细胞生理学中令人难以置信的多样性事件。根据我们的初步数据，我们假设细胞外基质通过 ¿3 和 ¿6 整合素控制 Notch 信号传导。本文描述的实验将探索这一假设，这样做将对我们理解细胞外基质、整合素和Notch信号传导如何合作不仅控制正常细胞生物学而且控制与癌症等疾病相关的病理细胞生物学产生巨大影响。