Role of Prox1 in liver development and liver homeostasis

Prox1 在肝脏发育和肝脏稳态中的作用

• 批准号: 7925808
• 负责人: Beatriz Sosa-Pineda
• 金额: $ 25.58万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925808
• 关键词: Adult; Affect; Architecture; Biliary; Cells; Congenital Abnormality; Development; Developmental Process; Embryo; Embryonic Development; Endoderm; Epithelium; Extrahepatic; Future; Generations; Genes; Health; Hepatic; Hepatocyte; Homeobox; Homeobox Genes; Homeostasis; Human; In Vitro; Knowledge; Laboratories; Learning; Liver; Liver diseases; Lobe; Malignant Epithelial Cell; Membrane; Molecular; Molecular Genetics; Morphogenesis; Morphology; Mouse Strains; Mus; Organ; Organogenesis; Pancreas; Population; Primary carcinoma of the liver cells; Primitive foregut structure; Process; Role; Staging; Stem cells; Structure; Therapeutic Uses; Tissues; bile duct; expectation; in vivo; malformation; migration; mouse model; novel; postnatal; research study; stem; tool

DESCRIPTION (provided by applicant): While our knowledge on early liver development increased considerably in the past decade, much remains to be learned on how the distinct regulators of liver organogenesis operate at the molecular level. This information is necessary not only to uncover how the function of a particular developmental regulator is required for certain developmental processes, but also to understand how its derailed activity could predispose to liver disease. Our initial studies of the mouse homeobox-gene Prox1 showed that its function is a crucial requirement for early liver morphogenesis and for hepatoblast proliferation (Sosa-Pineda et al., 2000). More recently, we demonstrated that Prox1 function is also necessary for late aspects of liver organogenesis and to maintain the integrity of this organ of adults. In this application, I put forth several molecular and genetic approaches to further our previous studies on the functional role of Prox1 in the developing mouse liver and to uncover how Prox1-expressing endoderm precursors contribute to liver organogenesis. In addition, by taking advantage of two novel mouse models generated in my laboratory I propose to uncover how the Prox1 function is required at postnatal stages for liver homeostasis. After completing the experimental approaches proposed in this application I expect to have gained valuable information on mammalian liver organogenesis and to uncover how certain molecular mechanisms contribute to preserve the integrity of this organ of adults. This information should be relevant to understand the molecular origin of some liver diseases and for studies aimed at differentiating stem into functional liver cells that could be used for therapeutic purposes. RELEVANCE: The basic structure of the liver starts to be established during embryogenesis and is completed at postnatal stages. Uncovering the molecular and cellular mechanisms that govern mammalian liver development should be highly significant to disclose the origin of human congenital liver malformations. Our previous studies of the mouse homeobox-containing Prox1 gene showed that its function is a crucial requirement for early liver morphogenesis. In this application, I put forth several molecular and genetic approaches to further our previous studies on the functional role of Prox1 in the developing mouse liver, to disclose how Prox1 function is required for postnatal liver homeostasis, and to uncover how Prox1-expressing endoderm precursors contribute to liver organogenesis. My long-term expectation is that the information obtained from these studies will be relevant to understand the molecular origin of certain liver diseases in humans.

描述（由申请人提供）：虽然我们对早期肝脏发育的了解在过去十年中大大增加，但关于肝脏器官发生的不同调节剂如何在分子水平上运作仍有很多东西需要了解。这些信息不仅对于揭示特定发育调节因子的功能是某些发育过程所必需的，而且对于了解其脱轨的活动如何可能导致肝脏疾病是必要的。 我们对小鼠同源框基因Prox 1的初步研究表明，其功能是早期肝脏形态发生和肝母细胞增殖的关键要求（Sosa-Pineda et al.，2000年）。最近，我们证明了Prox 1功能对于肝脏器官发生的后期方面以及维持成人肝脏器官的完整性也是必要的。 在本申请中，我提出了几种分子和遗传方法，以进一步我们以前的研究Prox 1在发育中的小鼠肝脏中的功能作用，并揭示Prox 1表达的内胚层前体如何有助于肝脏器官发生。此外，通过利用我实验室中产生的两种新型小鼠模型，我建议揭示Prox 1功能如何在出生后阶段用于肝脏稳态。 在完成本申请中提出的实验方法后，我希望获得有关哺乳动物肝脏器官发生的有价值的信息，并揭示某些分子机制如何有助于保护成年人肝脏器官的完整性。这些信息应该与理解某些肝脏疾病的分子起源以及旨在将干细胞分化为可用于治疗目的的功能性肝细胞的研究相关。 相关性：肝脏的基本结构在胚胎发育期间开始建立，并在出生后阶段完成。揭示哺乳动物肝脏发育的分子和细胞机制对揭示人类先天性肝脏畸形的起源具有重要意义。 我们以前的研究表明，小鼠同源框包含Prox 1基因的功能是早期肝脏形态发生的关键要求。在本申请中，我提出了几种分子和遗传学方法，以进一步我们以前的研究Prox 1在发育中的小鼠肝脏的功能作用，揭示如何Prox 1功能所需的出生后的肝脏稳态，并揭示如何Prox 1表达内胚层前体有助于肝脏器官发生。我的长期期望是，从这些研究中获得的信息将有助于了解人类某些肝脏疾病的分子起源。