Beta 1 integrins in erythropoiesis

描述（由申请人提供）：整合素是一种重要的蛋白质，用于整合细胞间的信号，并解释来自微环境的线索，极大地影响细胞行为。整合素在造血细胞和非造血细胞中广泛表达，并且在整个发育过程和成年期的细胞迁移行为中发挥重要作用。此外，整合素由于其作为双向信号传导机器的能力以及与其他整合素或生长因子受体和信号传导介质的“串扰”，可以诱导基因表达和其他细胞反应的变化。整合素在早期原始正常造血细胞中的作用已经确立，越来越多的证据表明它们在肿瘤细胞中也有重要作用。然而，它们在红细胞生成中的作用在很大程度上是描述性的，最重要的是，在使用抗体（Abs）或遗传模型时，数据呈现不一致。在我们最近的工作中，我们试图通过比较相关的遗传小鼠模型来澄清以前关于造血/红细胞生成中整合素伴侣丢失的一些模糊之处。虽然获得了新颖和重要的信息，但数据产生了新的问题。在这项资助中，利用我们先前整合素遗传模型的经验，我们希望利用创新的遗传模型组合，提供关于a和a4整合素在稳态和应激反应中末端e分化中的独特作用的明确数据（SA 1）。此外，关于整合素依赖的分子介质的信息也很不完整，许多分子链接也缺失。来自红细胞生成过程中其他重要参与者的信息如何通过红细胞上的整合素被截获以处理应激反应尚不清楚，将在SA2中讨论。最后，在我们的研究中，结合最先进的基因组工具和我们新的遗传模型（sa3），应该进一步阐明某些整合素控制红细胞生成终端步骤的复杂和组合相互作用，特别是在应激下。本研究中所描述的实验不仅确立了整合素在红细胞氧化应激反应和抗氧化稳态中作为一种新的、未被探索的角色，而且将为整合素在红细胞生成中的单一或组合作用的贡献提供一个更好的视角。此外，在我们的动物模型中进行的长期研究应该为整合素作为癌症治疗靶点提供必要的生物学知识。

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.