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

描述（由申请人提供）：本提案概述了一项旨在理解果蝇模型中年龄依赖性干细胞功能失调的实验策略。成年果蝇的肠上皮由常驻干细胞维持，这些干细胞形成了所有类型的肠上皮细胞。这些肠干细胞（ISCs）在组织损伤和衰老的反应中分裂，但似乎失去了对其增殖极限的控制。具体来说，衰老导致ISC过度增殖，这本身就类似于我们在哺乳动物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有助于阐明高等生物（如人类）中癌症的机制。我们将通过解决该领域的两个相关问题来填补我们目前对干细胞衰老理解的空白。在第一个目标中，我们将尝试理解的动态

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.