Beta 1 integrins in erythropoiesis

红细胞生成中的 Beta 1 整合素

• 批准号: 8536283
• 负责人: THALIA STAMATOYANNOPOULOS
• 金额: $ 32.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536283
• 关键词: Address; Adult; Aging; Animal Model; Animals; Antibodies; Antioxidants; Apoptosis Inhibitor; Applications Grants; BMP4; Behavior; Binding; Bioinformatics; Biological; Cancer Patient; Cell Cycle; Cells; Complex; Cues; Cysteine; Data; Development; Enzymes; Erythroid; Erythroid Cells; Erythropoiesis; Fluorouracil; Gene Expression; Generations; Genetic; Genetic Models; Genomics; Global Change; Glucocorticoids; Goals; Grant; Growth Factor Receptors; Hematopoiesis; Hematopoietic; Homeostasis; Homing; Infection; Inflammatory; Integrins; Intercept; Kinetics; Knowledge; Light; Link; Location; Longitudinal Studies; MAPK3 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Mitochondria; Modeling; Molecular; Molecular Profiling; Mus; Normal Cell; Oxidative Stress; Pathway interactions; Phenotype; Phenylhydrazines; Population; Proteins; Receptor Signaling; Recovery; Role; Signal Pathway; Signal Transduction; Site; Specificity; Stem cells; Stress; Testing; Therapeutic; Time; Work; base; biological adaptation to stress; cell behavior; cell motility; combinatorial; experience; fighting; in vivo; innovation; insight; interest; neoplastic cell; novel; phenylhydrazine; primitive cell; research study; response; stem; tool

DESCRIPTION (provided by applicant): Integrins are proteins important for integrating signals from cell to cell and for interpreting cues from their microenvironment that greatly influencing cell behavior. Integrins are broadly expressed in hematopoietic and non-hematopoietic cells alike and they have proven to be important players in the cells migratory behavior throughout development and in adulthood. In addition, integrins, because of their ability to serve as bidirectional signaling machines and because of their "cross talk" with other integrins, or growth factor receptors and signaling mediators, can induce changes in gene expression and other cellular responses. The role of integrins in early primitive normal hematopoietic cells is well established and accumulating evidence suggests that they also have important roles in neoplastic cells. However, their role in Erythropoiesis has been largely descriptive, and most importantly inconsistent in data presentation, using either antibodies (Abs) or genetic models. In our recent work we have attempted to clarify some of the previous ambiguities regarding the loss of ¿1 integrin partners in Hematopoiesis/Erythropoiesis by comparing relevant genetic murine models. Although novel and important information was gained, the data generated fresh questions. In this grant, capitalizing on our experience with the prior integrin genetic models, we hope to provide definitive data about the distinct roles of a and a4 integrins in terminal E-differentiation at homeostasis and in response to stress using innovative genetic model combinations (SA 1). Furthermore, there is only fragmentary information about the integrin-dependent molecular mediators and a lot of molecular links are missing. How the information from other important players in Erythropoiesis is intercepted through integrins on erythroid cells for addressing stress responses is unclear and will be addressed in SA2. Finally, incorporation of state of the art genomic tools in our studies with our new genetic models (SA 3) should shed further light on the complex and combinatorial interplay of certain integrins controlling terminal steps in Erythropoiesis, especially under stress. Experiments described in this Grant not only would establish the ¿1 integrins as a novel and unexplored player in oxidative stress response and anti-oxidant homeostasis of erythroid cells, but will provide an enhanced view on the contribution of single or combinatorial action of integrins in Erythropoiesis. Furthermore, long term studies in our animal models should provide essential biological knowledge needed when integrins are used as targets in cancer therapeutics.

描述（由适用提供）：整合素是蛋白质，对于整合细胞到细胞的信号以及解释其微环境的线索的蛋白质很重要，从而极大地影响了细胞行为。整联蛋白在造血和非山地肌细胞中广泛表达，事实证明它们是整个发育和成年期细胞迁移行为的重要参与者。此外，由于整联蛋白具有作为双向信号机的能力，并且由于它们与其他整合素或生长因子受体和信号传导介质的“交叉说话”可以诱导基因表达和其他细胞反应的变化。整联蛋白在早期原始正常造血细胞中的作用已经确定，积累的证据表明它们在肿瘤细胞中也具有重要作用。但是，它们在红细胞生成中的作用在很大程度上具有描述性，并且最重要的是使用抗体（ABS）或遗传模型在数据表示中不一致。在我们最近的工作中，我们试图通过比较相关的遗传鼠模型来阐明有关造血/红细胞增多蛋白的1个综合蛋白伴侣丧失的一些歧义。尽管获得了新颖和重要的信息，但数据产生了新的问题。在这笔赠款中，利用我们在先前的整合素遗传模型的经验中，我们希望提供有关A和A4整合素在稳态终端电子差异中的独特作用的确定数据，并使用创新的遗传模型组合来应对压力（SA 1）。此外，只有关于整联蛋白依赖性分子介质的碎片信息，并且缺少许多分子链接。尚不清楚，通过红细胞细胞上的整合素在红细胞细胞上的整联蛋白截获了其他重要参与者的信息尚不清楚，并且将在SA2中解决。最后，通过新的遗传模型（SA 3）将最先进的基因组工具纳入我们的研究中，应进一步阐明某些整合素的复杂和组合相互作用，以控制红细胞生成的终末步骤，尤其是在压力下。该赠款中描述的实验不仅会建立€1整合素作为红细胞细胞的氧化应激反应和抗氧化稳态的新颖和意外的玩家，而且还将对整联蛋白在红细胞动物中的单个或组合作用的贡献提供增强的看法。此外，当我们的动物模型中的长期研究应提供必要的生物学知识，而整合素被用作癌症治疗的靶标。