Defining the Pancreatic Progenitor Mesenchymal Niche

定义胰腺祖细胞间充质生态位

• 批准号: 8577465
• 负责人: JAN JENSEN
• 金额: $ 42.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577465
• 关键词: Adult; Behavior; Bioinformatics; Biology; Cell Separation; Cells; Computer Simulation; Data; Data Set; Development; Developmental Biology; Diabetes Mellitus; Doxycycline; Embryo; Epithelial; Epithelial Cells; Evolution; Explosion; Funding; Future; Generations; Genomics; Goals; Heterogeneity; In Vitro; Malignant neoplasm of pancreas; Mesenchymal; Mesenchyme; Mus; Natural regeneration; Pancreas; Pancreatic Diseases; Pancreatic Injury; Patients; Population; Production; Relative (related person); Research; Research Project Grants; Signal Transduction; Staging; Stem cells; Technology; Testing; Therapeutic; Tissues; Transgenic Mice; Translating; base; behavior influence; genetic manipulation; in vivo; innovation; interest; morphogens; novel; progenitor; programs; public health relevance; research study; self-renewal; stem; stem cell biology; therapeutic target

DESCRIPTION (provided by applicant): The recent explosion of interest in adult tissue-specific progenitor cells has reinforced the principle that progenitor cells never function autonomously; their behavior is always governed by signals emanating from their unique spatial niche. Translating this principle to the pancreas, we propose that successful therapeutic targeting of pancreatic stem/progenitor cells will require effective characterization and manipulation of their corresponding mesenchymal niche. We are therefore proposing an innovative and highly integrated research program to identify, characterize and manipulate the pancreatic progenitor mesenchymal niche in adult and embryonic pancreas. The proposal is based on our recent identification of both a low-abundance, self-renewing, multi-lineage epithelial progenitor cell population in adult mouse pancreas, and a corresponding mesenchymal niche cell capable of promoting progenitor expansion. Based on these exciting findings, we are proposing the following central hypotheses: First, that unique population of mesenchymal niche cells exist embryonic and adult mouse pancreas. Second, that niche identify is defined by the production and secretion of specific soluble morphogens. Third, that characterization of the niche cell "secretome" will allow the identification of specific morphogens responsible for regulating the proliferation, differentiation and self-renewal of embryonic and adult pancreatic progenitor cells. To test these hypotheses, we are proposing three Specific Aims. Specific Aims 1 and 2 share parallel approaches applied to the embryonic pancreas in Aim 1 and to normal and regenerating adult pancreas in Aim 2. For both of these Aims, we will characterize and quantify the relative abundance of different pancreatic mesenchymal cell subpopulations, test their ability to regulate the proliferative expansion, differentiation and sel-renewal of pancreatic epithelial progenitor cells, and identify relevant components of the niche "secretome" responsible for these effects. Having identified specific niche cell populations and associated secreted morphogens responsible for niche function, experiments in Aim 3 will seek to genetically manipulate adult pancreatic mesenchymal niche cells, using a combination of Cre/lox and rtTA/TRE technology for mesenchyme-specific, doxycycline-inducible expression of ActivinA and other secreted morphogens. Together, these Aims will provide an entirely novel and integrated view of pancreatic mesenchymal development and pancreatic niche biology, setting the stage for eventual therapeutic manipulation of the adult pancreatic progenitor mesenchymal niche.

描述（由申请人提供）：最近对成体组织特异性祖细胞的兴趣激增，强化了祖细胞永远不会自主发挥功能的原则；他们的行为总是受到来自其独特空间生态位的信号的控制。将这一原理应用到胰腺，我们提出，胰腺干/祖细胞的成功治疗靶向将需要对其相应的间充质生态位进行有效的表征和操作。因此，我们提出了一项创新且高度综合的研究计划，以识别、表征和操纵成人和胚胎胰腺中的胰腺祖细胞间充质生态位。该提议基于我们最近在成年小鼠胰腺中鉴定出的低丰度、自我更新、多谱系上皮祖细胞群，以及能够促进祖细胞扩增的相应间充质生态位细胞。基于这些令人兴奋的发现，我们提出以下中心假设：首先，胚胎和成年小鼠胰腺中存在独特的间充质生态位细胞群。其次，该生态位识别是由特定可溶性形态发生素的产生和分泌来定义的。第三，利基细胞“分泌组”的表征将允许识别特定的形态发生素 负责调节胚胎和成体胰腺祖细胞的增殖、分化和自我更新。为了检验这些假设，我们提出了三个具体目标。具体目标 1 和 2 共享应用于目标 1 中的胚胎胰腺和目标 2 中的正常和再生成人胰腺的并行方法。对于这两个目标，我们将表征和量化不同胰腺间充质细胞亚群的相对丰度，测试它们调节胰腺上皮祖细胞增殖扩张、分化和自我更新的能力，并鉴定 负责这些效应的生态位“分泌组”的相关成分。在确定了特定的生态位细胞群和负责生态位功能的相关分泌型成形素后，目标 3 中的实验将寻求对成人胰腺间质生态位细胞进行基因操作，结合使用 Cre/lox 和 rtTA/TRE 技术来实现间充质特异性、多西环素诱导型 ActivinA 和其他分泌型成形素的表达。总之，这些目标将为胰腺间质发育和胰腺生态位生物学提供全新且综合的观点，为成人胰腺祖细胞间质生态位的最终治疗操作奠定基础。