REGULATION OF ATROPHY-INDUCED PROGENITOR CELLS IN THE GASTRIC CORPUS

胃体中萎缩诱导的祖细胞的调节

• 批准号: 8695339
• 负责人: Jason C Mills
• 金额: $ 33.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-11 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8695339
• 关键词: Ablation; Acids; Adult; Affect; Age; Animals; Arthritis; Atrophic; Bioinformatics; Biological Assay; Blood; CD44 gene; Cancer Etiology; Cell Death; Cell Differentiation process; Cell Proliferation; Cell Surface Proteins; Cells; Cessation of life; Characteristics; Chronic; Data; Databases; Developing Countries; Disadvantaged; Disease; E-Cadherin; Epithelial; Epithelial Cells; Epithelium; Estrogens; Frequencies; Gastric Parietal Cells; Gastric ulcer; Gene Expression; Generations; Genes; Goals; Hematopoietic stem cells; Homeostasis; Hour; Human; Hyaluronan; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Intestines; Kinetics; Label; Learning; Ligands; Malignant Neoplasms; Mediator of activation protein; Metaplasia; Minority; Molecular; Molecular Genetics; Molecular Profiling; Mus; Organ; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Physiological; Population; Process; Pyloric antrum; Regulation; Relative (related person); Research; Risk; Role; STAT3 gene; Secondary to; Selective Estrogen Receptor Modulators; Signal Transduction; Site; Staging; Stem cells; Stomach; Stomach Diseases; System; Tamoxifen; Techniques; Time; Tissues; Toxic effect; Tweens; Undifferentiated; United States; Work; adult stem cell; cancer risk; cell behavior; cost; genetic pedigree; human disease; inhibitor/antagonist; innovation; killings; laser capture microdissection; malignant stomach neoplasm; progenitor; prospective; research study; response; response to injury; stem; stem cell differentiation; stem cell niche; stem cell population; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Despite recent breakthroughs in identifying prospective stem cell markers (e.g., LGR5) in the intestines and the gastric antrum, relatively little is known about the stem cells of the gastric (body) corpus epithelium. Our overall goal is t better characterize the corpus stem cell under normal conditions and in response to injury. Preliminary data show that the selective estrogen receptor modulator tamoxifen causes ablation of nearly all parietal cells, the acid-secreting lineage, in the mouse stomach within 3 days. Within 6 hours, parietal cells begin to die (atrophy), and progenitor cells in the isthmal stem cel niche of corpus gastric units begin to expand in response. We further find that: 1) the cell surface protein CD44 is required for normal stem cell homeostasis, because proliferation is halved in Cd44-/- relative to wildtype mice; and 2) CD44 marks the expanding isthmal progenitor population. CD44 activates STAT3 and is induced by ERK signaling. We show here that ERK and STAT3 are activated in early expanding progenitors, and levels of the ERK-induced transcription factor EGR1 peak at 3 days, in concert with maximal progenitor expansion. We hypothesize that parietal cell death leads to signals that activate the ERK pathway in isthmal stem/progenitor cells, which causes increased CD44 expression and increased proliferation. In Aim 1, we will determine whether ERK signaling is required for normal stem cell homeostasis and atrophy-induced expansion using both ERK pharmacological inhibition and pedigrees of mice with deficient (Egr1-/-) and overactive (Nab2-/-) ERK. In Aim 2, we will determine whether CD44 is required or sufficient for atrophy-induced progenitor expansion. We will examine kinetics of stem cell expansion in Cd44-/- mice, and we will either activate CD44 in wildtype mice ¿tamoxifen by injection of the CD44 ligand Hyaluronan or block CD44- Hyaluronan interactions with the inhibitor PEP-1. We will determine if CD44 induces STAT3 and/or if it is required for progenitor expansion. In Aim 3, we will isolate vehicle- and tamoxifen-treated CD44-expressing epithelial progenitor cells by FACS and laser-capture microdissection and then use RNA-Seq to generate gene expression profiles of the normal and atrophy-expanded progenitor cells that will then be integrated bioinformatically with our existing database of global gene expression in stem and progenitor cells. We will also perform limiting dilution assays to determine the stem cell frequency within the epithelial CD44 population. In humans, chronic inflammation can cause parietal cell atrophy, which in turn changes stem cell proliferation and differentiation. Atrophy predispose patients to gastric cancer, but changes in stem cells secondary to inflammation/injury are also an important and understudied aspect of adult diseases in multiple other tissues (e.g., hematopoietic stem cell differentiation changes in arthritis). Thus, the experiments proposed may help us begin to understand stem cell response to injury in multiple tissues and diseases. Finally, our new finding that the key drug tamoxifen causes gastric toxicity warrants further study in humans.

描述（通过应用程序证明）：尽管最近有饲料的前瞻性干细胞标记（例如LGR5）Altrum，但对胃（身体）副本的干细胞的相对知之甚少。损伤。他莫昔芬几乎在3天内在小鼠胃中消融几乎所有的壁细胞。 6 6小时，顶壁细胞开始死亡（萎缩），胃胃单位的iShmal茎生成源是正常干细胞稳态需要的细胞表面蛋白CD44，因为CD44在CD44中的增殖需要减半 - / - 野生型小鼠和2）CD44标志着iShmal投影仪的扩展，并通过ERK信号诱导。 EGR1在3天达到峰值，与最大祖细胞的扩张一致。我们假设壁细胞死亡会导致激活地峡茎/祖细胞中ERK途径的信号使用ERK Al抑制和萎缩诱导的膨胀的正常干细胞稳态和萎缩的ERK信号传导，并在AIM 2中确定CD44是否需要CD44。或n cd44 - / - 小鼠，我们将在野生型小鼠中激活CD44 tamoxifen通过INGALURONAN或CD44-透明质酸与抑制剂PEP-1的相互作用，或者在AIM 3中的祖细胞膨胀所必需。然后，为了生成正常萎缩术中的祖细胞的基因表达，然后将生物信息与我们在茎和祖细胞中的全局表达的生物敏化。慢性炎症会引起顶叶细胞萎缩，进而改变干细胞的胃癌，但炎症/损伤的干细胞的变化也会变化。关节炎）因此，所提出的经验可以帮助我们了解茎的茎。