Dissecting the Role of Podxl in Hepatic Stellate Cells in Liver Development and Regeneration

剖析 Podxl 在肝星状细胞中肝脏发育和再生中的作用

基本信息

  • 批准号:
    10246180
  • 负责人:
  • 金额:
    $ 3.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-08 至 2023-07-07
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT The mechanisms that control hepatic stellate cell (HSC) migration during liver development and regeneration are not well understood. This knowledge gap has hindered the generation of new therapies and the improvement of patient outcome for various developmental disorders such as congenital hepatic fibrosis and fibrosing liver diseases such as alcoholic and non-alcoholic steatohepatitis. The critical need addressed in this proposal is to identify and characterize factors that influence HSC migration during development and in regeneration. HSCs migrate to the liver from the septum transversum early in vertebrate development. Once in the liver, HSCs secrete growth factors and cytokines, such as TGF-ß and FGF10, that promote hepatocyte proliferation. In the healthy adult liver, HSCs’ main function is to act as a storage site for vitamin A and regulate extracellular matrix (ECM) turnover. When the liver is injured, HSCs migrate to the liver injury site where they secrete ECM, growth factors, and cytokines to promote liver regeneration. Little is known about the factors involved in HSC migration into the liver during development and throughout the liver in response to injury. My long-term goal is to define mechanisms of liver development and regeneration, providing a foundation for improved therapies and patient outcomes for congenital disorders and fibrotic liver diseases. The overall objective of this proposal is to define mechanisms that control HSC behavior during development and regeneration. The central hypothesis in this proposal is that podxl regulates HSC migration to the liver during normal development (Aim 1), and within the liver in response to injury (Aim 2). Podxl is a highly sialylated and glycosylated transmembrane protein that is known to promote migration of several cell types, including hematopoietic stem cells and cancer cells. Several studies have shown that podxl is highly expressed in zebrafish HSCs, and our preliminary data demonstrates that knockdown of podxl in zebrafish during development results in fewer HSCs in the liver. In this study, the aim is to determine the role of podxl in HSCs during development and regeneration. A podxl mutant and overexpression line will be created to determine the role and mechanism of podxl in development. The working hypothesis is that Podxl promotes HSC migration by interaction of its DTHL motif with the actin-binding protein Moesin. In addition, homologous recombination will be used to create an HSC-specific Cre line that can be used to knock down genes in HSCs. This new HSC expressing Cre line will be used to knock down podxl in HSCs and determine how that influences their migration to liver injury sites and subsequent hepatocyte proliferation. This project involves generating novel genetic and imaging tools, which will be instrumental for my career development. Understanding the role of podxl in HSC migration during development and regeneration is significant because it will provide a foundation for generating new treatments for chronic liver diseases.
项目总结/摘要 肝发育过程中肝星状细胞(HSC)迁移的调控机制, 再生是不太清楚的。这种知识差距阻碍了新疗法的产生, 改善各种发育障碍如先天性肝纤维化的患者结果, 纤维化肝病,如酒精性和非酒精性脂肪性肝炎。本报告所述的关键需求 建议是确定和表征影响HSC迁移的因素,在发展过程中, 再生在脊椎动物发育的早期,HSC从横隔迁移到肝脏。一次 在肝脏中,HSC分泌生长因子和细胞因子,如TGF-β和FGF 10,其促进肝细胞 增殖在健康成人肝脏中,HSC的主要功能是作为维生素A的储存位点,并调节 细胞外基质(ECM)周转。当肝损伤时,HSC迁移到肝损伤部位, 分泌ECM、生长因子和细胞因子以促进肝再生。人们对这些因素知之甚少 参与HSC在发育过程中迁移到肝脏中以及响应于损伤而迁移到整个肝脏中。我 长期目标是确定肝脏发育和再生的机制,为 改善先天性疾病和纤维化肝病的治疗和患者结局。整体 该提案的目的是定义在发育过程中控制HSC行为的机制, 再生该建议的中心假设是,podxl调节HSC向肝脏的迁移, 正常发育(目标1)和肝脏内对损伤的反应(目标2)。Podxl是高度唾液酸化的, 糖基化跨膜蛋白,已知其促进几种细胞类型的迁移,包括 造血干细胞和癌细胞。几项研究表明,podxl是高表达的, 我们的初步数据表明,斑马鱼HSC中podxl的敲低, 发育导致肝脏中的HSC较少。在这项研究中,目的是确定podxl在HSC中的作用, 在发育和再生过程中。将创建podxl突变体和过表达系以确定podxl的表达。 podxl在发育中的作用及机制工作假设是Podxl促进HSC迁移, DTHL基序与肌动蛋白结合蛋白膜突蛋白的相互作用。此外,同源重组将 用于创建HSC特异性Cre系,其可用于敲低HSC中的基因。新的HSC 表达Cre的细胞系将用于敲低HSC中的podxl,并确定其如何影响它们的迁移 肝损伤部位和随后的肝细胞增殖。该项目涉及产生新的遗传和 成像工具,这将有助于我的职业发展。了解podxl在HSC中的作用 在开发和再生过程中的迁移是重要的,因为它将为生成 慢性肝病的新疗法。

项目成果

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Alexis Noel Ross其他文献

Alexis Noel Ross的其他文献

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{{ truncateString('Alexis Noel Ross', 18)}}的其他基金

Dissecting the Role of Podxl in Hepatic Stellate Cells in Liver Development and Regeneration
剖析 Podxl 在肝星状细胞中肝脏发育和再生中的作用
  • 批准号:
    10389757
  • 财政年份:
    2020
  • 资助金额:
    $ 3.25万
  • 项目类别:
Dissecting the Role of Podxl in Hepatic Stellate Cells in Liver Development and Regeneration
剖析 Podxl 在肝星状细胞中肝脏发育和再生中的作用
  • 批准号:
    10417249
  • 财政年份:
    2020
  • 资助金额:
    $ 3.25万
  • 项目类别:

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