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Reelin signaling and mammary gland development

Reelin 信号传导与乳腺发育

基本信息

批准号：
7905064
负责人：
ELLEN M. CARPENTER
金额：
$ 7.62万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-03 至 2011-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The reelin signaling pathway has been identified as a critical regulator of cell positioning in the developing central nervous system. Reelin binds to the low-density lipoprotein receptors ApoER2 and VLDLR that are expressed on the surfaces of migrating cells. Reelin signaling induces phosphorylation of the intracellular adaptor protein Dab1, triggering a cascade that modulates cytoskeletal activity ultimately regulating cell migration. Reelin signaling has been implicated in the development of a number of central nervous system regions including the cortex, hippocampus, cerebellum and spinal cord. Preliminary evidence from my laboratory suggests that reelin signaling and/or members of the reelin signaling pathway may also function outside the nervous system. Using a Dab1 reporter mouse, we have identified several novel regions where reelin signaling might be utilized, including the developing mammary glands and limbs. This finding suggests that reelin signaling may modulate cell migration and positioning in multiple tissues in developing embryos. The proposed study will address the role of reelin signaling in the mammary gland. First, we will determine when and where members of the reelin signaling pathway are expressed in the developing mammary gland. Second, we will address whether reelin signaling can guide the migration and positioning of mammary epithelial cells. Third, we will determine whether reelin signaling is required for the in vivo migration of mammary gland cells. Together, these studies will explore possible roles for reelin signaling in regulating cell migration and positioning outside the nervous system. Understanding how cell positioning and migration are regulated is critical to understanding how an embryo develops, but it is also critical in understanding the biology of cancer cells. Breast cancers involve the unchecked proliferation and migration of mammary gland cells. Understanding how this migration is regulated during normal development may provide avenues for designing strategies to limit or arrest this migration in invasive breast cancers. PUBLIC HEALTH RELEVANCE: Cell migration is the process by which cells move from where they are born to where they are needed in a developing embryo. This process is critically important for normal embryonic development because most cells migrate to form and colonize tissues of the body. Like cells in developing embryos, cancer cells are highly migratory and invasive; thus, by characterizing the molecular cascades involved in regulating cell migration during normal development, we hope to identify elements that may be targeted during cancer treatment to reduce or inhibit the migration of these cells.

描述（由申请人提供）：reelin 信号通路已被确定为发育中的中枢神经系统中细胞定位的关键调节因子。 Reelin 与迁移细胞表面表达的低密度脂蛋白受体 ApoER2 和 VLDLR 结合。 Reelin 信号传导诱导细胞内衔接蛋白 Dab1 磷酸化，引发级联反应，调节细胞骨架活性，最终调节细胞迁移。 Reelin 信号传导与许多中枢神经系统区域的发育有关，包括皮质、海马体、小脑和脊髓。我实验室的初步证据表明，reelin 信号传导和/或 reelin 信号传导途径的成员也可能在神经系统之外发挥作用。使用 Dab1 报告小鼠，我们发现了几个可能利用 reelin 信号传导的新区域，包括正在发育的乳腺和四肢。这一发现表明，reelin 信号传导可能会调节发育胚胎中多个组织中的细胞迁移和定位。拟议的研究将探讨 reelin 信号在乳腺中的作用。首先，我们将确定 reelin 信号通路成员在发育中的乳腺中表达的时间和地点。其次，我们将讨论 reelin 信号传导是否可以指导乳腺上皮细胞的迁移和定位。第三，我们将确定乳腺细胞体内迁移是否需要 reelin 信号传导。这些研究将共同探索 reelin 信号在调节神经系统外细胞迁移和定位中的可能作用。了解细胞定位和迁移的调节方式对于了解胚胎如何发育至关重要，对于了解癌细胞的生物学也至关重要。乳腺癌涉及乳腺细胞不受控制的增殖和迁移。了解在正常发育过程中如何调节这种迁移可能为设计限制或阻止浸润性乳腺癌中这种迁移的策略提供途径。公共卫生相关性：细胞迁移是细胞从出生地移动到发育中胚胎需要它们的地方的过程。这个过程对于正常胚胎发育至关重要，因为大多数细胞会迁移形成并定殖身体组织。与发育中胚胎中的细胞一样，癌细胞具有高度迁移性和侵袭性。因此，通过表征正常发育过程中调节细胞迁移的分子级联，我们希望识别出在癌症治疗过程中可能靶向的元素，以减少或抑制这些细胞的迁移。