Nutrient regulation of stem cell mediated intestinal renewal in Drosophila

描述（由申请人提供）： 组织的自我更新对成年生物体的生存能力是必不可少的。在肠道中，更新过程具有内在的灵活性，可以通过改变增殖/死亡平衡来适应外部影响。然而，触发适应的信号和重新平衡体内平衡的机制实际上尚未探索。随着最近发现，多能干细胞更新肠内膜在成年果蝇中肠，强大的优势，果蝇系统优越的遗传工具，先进的细胞分析，和高实验的易处理性，可以应用于组织的动态平衡是如何调节的突出问题。这项研究的最终目标是了解死亡和增殖如何在组织内协调以实现稳态，并揭示实现稳态灵活性的机制。这项建议的重点是营养驱动的粘膜重塑，肠道适应的一个范例。结合遗传和细胞的方法将被用来检查的假设，不同的系统和本地机制调节营养驱动的适应。目的1将描述营养素如何改变肠道内稳态中增殖/死亡平衡的空间和时间分布。目的2将研究系统的，营养敏感的内分泌信号，特别是胰岛素和果蝇神经肽Y同源物，在稳态重塑中的作用。目的3将通过确定肠上皮细胞如何通过组织结构控制附近干细胞的增殖来研究局部细胞相互作用的作用，最终通过遗传筛选来识别新的基因，包括营养敏感和不敏感的基因，促进短程稳态控制。这些研究的结果将为肠道适应的途径提供新的线索。在大卫比尔德博士和约翰福特博士的共同指导下，这两个领域的领导者，候选人将获得在胃肠道生理学，干细胞生物学和遗传筛查的新领域的专业知识，同时追求她在上皮组织动力学的长期兴趣。这个研究和培训计划将促进候选人的进展，以帮助她建立分子和细胞生物学的加州大学伯克利分校部门内的独立和互补的研究项目的自主权。 公共卫生相关性：肠道自我更新的能力可能会被伤害和疾病所压倒，导致营养吸收受损和长期静脉喂养。为了开发更好的治疗方法，我们需要更多地了解控制肠道更新的基本基因和过程。研究果蝇的肠道更新，一个简单的动物模型，将产生新的线索，可以在哺乳动物中进一步探索。

DESCRIPTION (provided by applicant): Tissue self renewal is essential to the viability of the adult organism. In the intestine, the renewal process has built-in flexibility to adapt to external influences by altering the proliferation/death equilibrium. However, the signals that trigger adaptation and the mechanisms that re-equilibrate homeostatic balance are virtually unexplored. With the recent discovery that multipotent stem cells renew the intestinal lining in the adult Drosophila midgut, the powerful advantages of the Drosophila system-superior genetic tools, sophisticated cellular analysis, and high experimental tractability-can be applied to the outstanding problem of how tissue homeostasis is dynamically regulated. The ultimate goals of this research are to understand how death and proliferation are coordinated within tissues to achieve homeostasis and to uncover the mechanisms that enable homeostatic flexibility. This proposal focuses on nutrient-driven mucosal remodeling, a paradigm of intestinal adaptation. Combined genetic and cellular approaches will be used to examine the hypothesis that distinct systemic and local mechanisms regulate nutrient-driven adaptation. Aim 1 will characterize how nutrients alter the spatial and temporal profile of the proliferaton [sic]/death balance in intestinal homeostasis. Aim 2 will investigate the role of systemic, nutrient-sensitive endocrine signals, particularly insulin and a Drosophila neuropeptide Y homolog, in homeostatic remodeling. Aim 3 will investigate the role of local cellular interactions by determining how enterocytes act through tissue structure to control the proliferation of nearby stem cells, culminating in a genetic screen to identify novel genes, both nutrient-sensitive and -insensitive, that promote short-range homeostatic control. The results from these studies will shed new light on the pathways that underlie intestinal adaptation. Under the mentorship of Dr. David Bilder and co-mentorship of Dr. John Forte, both leaders in the irrespective fields, the candidate will gain expertise in newer areas of GI physiology, stem cell biology, and genetic screening while pursuing her long-standing interest in epithelial tissue dynamics. This research and training plan will faciliate [sic] the candidate's progression to autonomy by helping her establish an independent and complementary research project within the UC Berkeley Department of Molecular and Cell Biology. PUBLIC HEALTH RELEVANCE: The ability of the intestine to renew itself can be overwhelmed by injury and disease, leading to impaired nutrient absorption and long-term intravenous feeding. To develop better therapies, we need to know more about the basic genes and processes that control intestinal renewal. Studying intestinal renewal in fruit flies, a simple animal model, will generate new leads that can be explored further in mammals.