MMP regulation of stem cell proliferation in the Drosophila ovary

MMP 对果蝇卵巢干细胞增殖的调节

• 批准号: 8672664
• 负责人: Andrea W Page-McCaw
• 金额: $ 7.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-05 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672664
• 关键词: Adult; Alleles; Apical; Biology; Caliber; Cancer Biology; Cell Proliferation; Cells; Chimeric Proteins; Cyst; Data; Daughter; Development; Developmental Biology; Drosophila genus; Epithelium; Erinaceidae; Event; Extracellular Matrix; Family; Female; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Graafian Follicles; Growth; Heparan Sulfate Proteoglycan; Inflammation; Intestines; Lead; Left; Ligands; Lipids; Lipoproteins; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Modeling; Mus; Organ; Ovary; Pathway interactions; Peptide Hydrolases; Phenotype; Postdoctoral Fellow; Proliferating; Proteins; RNA Interference; Regenerative Medicine; Regulation; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Site; Skin; Somatic Cell; Stem cells; Systems Analysis; Testing; Tissues; Training; Vertebrates; cell type; daughter cell; egg; experience; extracellular; genetic analysis; mutant; particle; precursor cell; protein transport; public health relevance; research study; smoothened signaling pathway; stem cell fate; tumor progression

DESCRIPTION (provided by applicant): In the Drosophila ovary, developing follicles are composed of somatic follicle cells surrounding germline cysts that will become the egg. The follicle cells derive from somatic stem cells, which give rise to follicle cell precursors, which i turn differentiate into mature follicle cells. It has been reported that the Wnt (Wg) and Hedgehog (Hh) signaling pathways stimulate somatic stem cell proliferation in the Drosophila ovary, as the hyper-activation of these pathways results in excess follicle cells. These signals are produced by cells that are 3-5 cell diameters away from the stem cells, raising the question of how the signals are transported to the responding stem cells. In our continuing studies of the extracellular matrix-degrading MMP family of proteases, we have observed that when Mmp2 function is lost conditionally in adult females, the follicle stem cells over-proliferate in the ovry. This phenotype is consistent with Mmp2 inhibiting the Wg and/or Hh signaling pathway. This R03 proposal describes a small study to determine how Mmp2 regulates somatic stem cell proliferation. In Aim1, we will determine if Wg, Hh, or both pathways are altered, through analysis of genetic interactions and gene expression patterns. In Aim 2, we will determine how Mmp2 mediates long-range signaling over several cell diameters, by asking if Mmp2-GFP is itself transported, and testing candidate transport models including lipid particle transport, HSPG transport, and GPI-anchor mediated transport. We are well situated to perform these studies, as the PI has been investigating Drosophila MMPs for a decade and originally trained in the Drosophila ovary, and the postdoc performing the experiments has experience with stem cell proliferation in the Drosophila ovary. Additionally, our lab is located immediately adjacent t labs that study wnt and hh signaling in vertebrates. Our studies have high significance, as all three of these pathways - MMP, Wg, and Hh - have been implicated in tumor progression, and Wnt signaling is central to stem cell regulation in epithelia such as skin and intestine. Our findings propose a new model that MMPs limit these growth-promoting signals to stem cells. We expect the small study proposed here will lay the foundation for a larger mechanistic analysis of how MMPs regulate stem cell proliferation, in both development and cancer.

描述（由申请方提供）：在果蝇卵巢中，发育中的卵泡由体细胞卵泡细胞组成，围绕着将成为卵子的生殖细胞囊。滤泡细胞来源于体干细胞，体干细胞产生滤泡细胞前体，然后分化为成熟的滤泡细胞。据报道，Wnt（Wg）和Hedgehog（Hh）信号通路刺激果蝇卵巢中的体干细胞增殖，因为这些通路的过度激活导致过多的卵泡细胞。这些信号是由距离干细胞3-5个细胞直径的细胞产生的，这就提出了信号如何被转运到响应干细胞的问题。 在我们对降解细胞外基质的MMP蛋白酶家族的持续研究中，我们观察到当成年女性中Mmp 2功能有条件地丧失时，卵泡干细胞在卵巢中过度增殖。该表型与Mmp 2抑制Wg和/或Hh信号传导途径一致。R 03提案描述了一项小型研究，以确定Mmp 2如何调节体干细胞增殖。在Aim 1中，我们将通过分析遗传相互作用和基因表达模式来确定Wg，Hh或两种途径是否发生改变。在目标2中，我们将确定Mmp 2如何在几个细胞直径上介导远程信号传导，通过询问Mmp 2-GFP本身是否被转运，并测试候选转运模型，包括脂质颗粒转运，HSPG转运和GPI锚定介导的转运。 我们处于很好的位置进行这些研究，因为PI已经研究果蝇MMPs十年了，最初在果蝇卵巢中接受过培训，并且进行实验的博士后具有果蝇卵巢中干细胞增殖的经验。此外，我们的实验室紧邻研究脊椎动物中wnt和hh信号的t实验室。 我们的研究具有很高的意义，因为所有这三种途径- MMP，Wg和Hh -都与肿瘤进展有关，并且Wnt信号传导对上皮细胞（如皮肤和肠）中的干细胞调节至关重要。我们的研究结果提出了一个新的模型，MMPs限制了这些促进干细胞生长的信号。我们希望这里提出的小型研究将为MMPs如何在发育和癌症中调节干细胞增殖的更大机制分析奠定基础。