Beta 1 integrins in erythropoiesis

描述(申请人提供)：整合素是一种蛋白质，对于整合细胞与细胞之间的信号，以及从微环境中解释极大影响细胞行为的信号非常重要。整合素广泛表达于造血细胞和非造血细胞中，已被证明在细胞发育和成年期的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机器的能力，以及由于它们与其他整合素或生长因子受体和信号媒介的“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得到很好的证实，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，最重要的是在数据呈现方面不一致，使用抗体(Abs)或遗传模型。在我们最近的工作中，我们试图通过比较相关的小鼠遗传模型来澄清先前关于在造血/红细胞生成中失去整合素伙伴的一些模棱两可的说法。虽然获得了新的和重要的信息，但这些数据产生了新的问题。在这笔赠款中，我们希望利用我们先前的整合素遗传模型的经验，提供关于a和A4整合素在E末端分化中的不同作用的明确数据，并使用创新的遗传模型组合(SA 1)来响应压力。此外，关于整合素依赖的分子介体的信息还很零碎，许多分子连接缺失。来自红细胞生成中其他重要参与者的信息是如何通过红系细胞上的整合素被拦截以应对应激反应的尚不清楚，将在SA2中解决。最后，将最先进的基因组工具与我们的新遗传模型(SA 3)结合起来，将进一步揭示控制红细胞生成末端步骤的某些整合素的复杂和组合相互作用，特别是在应激条件下。这项授权中描述的实验不仅将建立整合素作为一个新的和未被探索的角色，在红系细胞的氧化应激反应和抗氧化动态平衡中，而且将提供关于整合素在红细胞生成中单一或组合作用的更好的观点。此外，在我们的动物模型中的长期研究应该提供当整合素被用作癌症治疗的靶点时所需的基本生物学知识。

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.