Functional examination of age-related stem cell dysfunction in the Drosophila gut

果蝇肠道中与年龄相关的干细胞功能障碍的功能检查

• 批准号: 9185251
• 负责人: Andrey Avanesov
• 金额: $ 6.98万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185251
• 关键词: Address; Adult; Age; Aging; Antibodies; Cancer Model; Cell Aging; Cell Communication; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Chemical Structure; Computing Methodologies; Cues; Development; Drosophila genus; Drosophila melanogaster; Enterochromaffin Cells; Environment; Epithelial Cells; Functional disorder; Gastrointestinal tract structure; Gene Expression; Genetic; Goals; Homeostasis; Human; Individual; Insulin; Intestines; Longevity; Longevity Pathway; Lung; Malignant Neoplasms; Mediating; Methods; Midgut; Modeling; Molecular; Molecular Profiling; Monitor; Organism; Pathologic; Pathway interactions; Phenotype; Protocols documentation; Reagent; Regulation; Reporter; Research; Role; Signal Transduction; Statistical Data Interpretation; Stem cells; Stress; System; Techniques; Testing; Tissues; Transgenes; Transgenic Organisms; adult stem cell; age related; analog; base; cell type; detection of nutrient; emerging adult; experience; experimental study; feeding; fly; gene repair; inhibitor/antagonist; insight; intestinal epithelium; longevity gene; molecular marker; novel; novel therapeutics; public health relevance; response; small molecule; tool

DESCRIPTION (provided by applicant): This proposal outlines an experimental strategy aimed at understanding age-dependent dysregulation of stem cell function in the Drosophila model. The adult Drosophila intestinal epithelium is maintained by resident stem cells which contribute to all gut epithelial cell types. These intestinal stem cells (ISCs) divide in response o tissue damage and aging, but appear to lose control of their proliferative limit. Specifically, agig leads to ISC hyperproliferation, which is in itself similar to pathological conditions we find in mammalian models of cancer. Thus, understanding the mechanisms for age-associated stem cell dysfunction may illuminate on the mechanisms of cancer in higher organisms, such as humans. We will begin filling gaps in our current understanding of stem cell aging by addressing two relevant problems in the field. In the first aim, we will attempt to understand the dynamics of gut aging, specifically focusing on the contribution of cell autonomous and cell non-autonomous aging cues on ISC aging and hypeproliferation. We will utilize well established methods in Drosophila system which will allow us to genetically manipulate the ISCs and their lineage in the gut. We will also use antibodies that reveal the rate of gut cell aging. Our second aim will expand on the new techniques in metabolite profiling to characterize the endogenous small molecule content of the aging environment in flies. We will then use computational methods and stringent statistical analysis, which efficiently identifies the most probable longevity candidates and will test their role on lifespan and stem cell aging. While our metabolite profiling may offer structural information of small molecule regulators of the stem cell aging, the complementary gene expression studies may illuminate on upstream genetic circuitries which can be functionally analyzed in cell-specific manner in the fly gut.

描述（由申请人提供）：该提案概述了一种实验策略，旨在了解果蝇模型中干细胞功能的年龄依赖性失调。成年果蝇肠上皮由常驻干细胞维持，这有助于所有肠道上皮细胞类型。这些肠道干细胞（ISC）在反应O组织损伤和衰老中分裂，但似乎失去了对其增殖极限的控制。具体而言，AGIG导致ISC高增殖，这本身就是类似于我们在癌症模型中发现的病理状况。因此，了解与年龄相关的干细胞功能障碍的机制可能会阐明较高生物体（例如人类）癌症的机制。我们将通过解决该领域的两个相关问题来开始填补我们当前对干细胞衰老的理解的空白。在第一个目标中，我们将尝试了解 肠道衰老，专门针对细胞自主和细胞非自主衰老对ISC衰老和催眠的贡献。我们将在果蝇系统中利用良好的方法，这将使我们能够在肠道中遗传操纵ISC及其谱系。我们还将使用揭示肠道细胞衰老速率的抗体。我们的第二个目标将扩展代谢物分析中的新技术，以表征苍蝇衰老环境的内源性小分子含量。然后，我们将使用计算方法和严格的统计分析，该分析有效地识别了最可能的寿命 并将测试它们在寿命和干细胞衰老中的作用。尽管我们的代谢产物分析可能会提供干细胞衰老的小分子调节剂的结构信息，但互补的基因表达研究可能会在上游遗传循环系统上照亮，这些循环循环可以在蝇肠中以细胞特异性方式进行功能分析。