Notch/Robo Regulated Mechanisms Governing Cell Fate Acquisition

项目主任/首席调查员(Hinck，Lindsay，E.) 在理解组织特异性干/祖细胞的作用和它们的能力方面存在着根本的差距 为了分裂和复兴。在乳房等组织中，这些细胞经历了膨胀的生长和 每一次怀孕都有不同的表现。然而，调控产生双核、产奶的机制 人们对肺泡细胞知之甚少。在弥合这一知识鸿沟之前，我们将无法支持 有相当数量的妇女产奶量不足。这项研究的长期目标是 了解哺乳动物如何利用干细胞/祖细胞来建立乳汁供应。最近，它被发现 在乳腺泡形成过程中，很大一部分细胞变成多倍体，这是牛奶所需的过程 制作。这项建议的目的是确定调节多倍体产生的信号通路 细胞通过内复制反应复制应激产生的DNA损伤，并确定 这些途径对牛奶产量的影响。中心假说是机器人调节的缺口信号 管理DNA损伤、分化反应和对肺泡的反应所发生的内复制 祖细胞的扩增和分化。我们的假设是基于我们自己的初步数据 对肺泡形成和Notch信号的差异调节，以及Robo/Notch信号共同调节 对DNA损伤的反应，我们发现这种反应发生在肺泡形成过程中。这背后的理由是 建议是，识别这些途径将允许进行干预，无论是药物干预还是饮食干预，即 促进肺泡发育和产奶量。在强劲的初步数据的指导下，三个假设将 测试有三个目的：1)Robo1通过限制一个或多个缺口的激活来促进分化 AVP中的受体。2)ROBO2通过激活一个或多个Notch受体的信号来抑制分化 直接或通过Robo1行动。3)复制压力，发生在扩展阶段 怀孕，是DNA损伤的来源，触发DNA损伤分化反应和 由Robo/Notch信号控制的内复制。这项拟议的研究意义重大，因为它将 确定增加牛奶产量的新方法。拟议的研究具有创新性，因为我们提出了 利用干细胞/祖细胞可以提高产奶量。以前的研究主要集中在 催乳素途径，只产生有明显副作用的药物。拟议的研究将 对产奶量不足的妇女及其没有收获好处的孩子产生积极影响 这种“液态黄金”。 小灵通398(01/18版批准至2020年3月31日)页面续格式页面

Program Director/Principal Investigator (Hinck, Lindsay, E.): There is a fundamental gap in understanding the role of tissue specific stem/progenitor cells and their capacity for division and renewal. In tissues such as the breast, these cells undergo expansive growth and differentiation with every pregnancy. Yet, mechanisms regulating the generation of binucleated, milk-producing alveolar cells are scarcely understood. Until this knowledge gap is closed, we will be unable to support the substantial number of women who produce insufficient milk. The long-term goal of this research is to understand how mammals harness stem/progenitor cells to build a milk supply. Recently, it was discovered that a large fraction of cells become polyploid during mammary alveologenesis, a process required for milk production. This proposal's objective is to identify the signaling pathways regulating the generation of polyploid cells via endoreplication in response to DNA damage generated by replication stress, and determine the impact of these pathways on milk production. The central hypothesis is that ROBO-regulated NOTCH signaling governs the DNA damage differentiation response and endoreplication that occurs in response to alveolar progenitor cell expansion and differentiation. Our hypothesis is based on our own preliminary data that ROBOs differentially regulate alveologenesis and Notch signaling, and that, together, Robo/Notch signaling regulates the response to DNA damage, which we find occurring during alveologenesis. The rationale underlying this proposal is that the identification of these pathways will allow for interventions, pharmacological or dietary, that improve alveolar development and milk production. Guided by strong preliminary data, three hypotheses will be tested in three Aims: 1) ROBO1 promotes differentiation by restricting the activation of one or more NOTCH receptors in AVPs. 2) ROBO2 inhibits differentiation by activating the signaling of one or more Notch receptors either directly or by acting through ROBO1. 3) Replication stress, occurring during the expansion phase of pregnancy, is the source of DNA damage, triggering the DNA damage differentiation response and endoreplication that is governed by Robo/Notch signaling. The proposed research is significant because it will identify new methods for increasing milk production. The proposed research is innovative because we propose that harnessing stem/progenitor cells can enhance milk production. Previous studies have focused on the prolactin pathway and only yielded drugs with significant negative side effects. The proposed research will have a positive impact for women who produce insufficient milk and their children who do not reap the benefits of this “liquid gold”. PHS 398 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page