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Defining the Pancreatic Progenitor Mesenchymal Niche

定义胰腺祖细胞间充质生态位

基本信息

批准号：
8719991
负责人：
JAN JENSEN
金额：
$ 40.62万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2015-06-30
项目状态：
已结题

项目摘要

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(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运作的原则；它们的行为总是由其独特的空间利基发出的信号所支配。将这一原理转化到胰腺，我们认为成功的治疗靶向胰腺干细胞/祖细胞将需要有效地表征和操纵它们相应的间充质生态位。因此，我们提出了一项创新和高度集成的研究计划，以识别、表征和操纵成人和胚胎胰腺的胰腺祖细胞间充质生态位。这一建议是基于我们最近在成年小鼠胰腺中发现了一个低丰度、自我更新的多谱系上皮祖细胞群体，以及相应的能够促进祖细胞扩张的间充质生态位细胞。基于这些令人兴奋的发现，我们提出了以下中心假设：第一，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，生态位识别是由特定的可溶形态原的产生和分泌来定义的。第三，利基细胞“分泌体”的特征将有助于识别特定的形态原负责调节胚胎和成人胰腺前体细胞的增殖、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。特定的AIMS 1和2在AIM 1中应用于胚胎胰腺，在AIM 2中应用于正常和再生的成人胰腺。对于这两个目标，我们将表征和量化不同的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、分化和自我更新的能力，并确定与这些作用相关的小生境“分泌体”的相关成分。在确定了特定的生态位细胞群体和相关的与生态位功能相关的分泌形态因子后，目标3的实验将寻求通过基因操作成人胰腺间充质生态位细胞，使用Cre/lox和RTTA/Tre技术相结合的方法，获得间充质特异性的、多西环素诱导的ActivinA和其他分泌形态因子的表达。总之，这些目标将为胰腺间充质发育和胰腺生态位生物学提供一个全新的、完整的视角，为最终治疗成人胰腺祖细胞间充质生态位奠定基础。