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至关重要。在肠道中，更新过程具有内在的灵活性，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动态平衡的机制实际上还没有被探索。随着最近发现多能干细胞更新成年果蝇中肠的肠壁，果蝇系统的强大优势--优越的遗传工具、复杂的细胞分析和高度的实验可控性--可以应用于组织动态平衡如何被动态调节的突出问题。这项研究的最终目标是了解组织内死亡和增殖是如何协调的，以实现动态平衡，并揭示实现动态平衡灵活性的机制。这项建议的重点是营养驱动的粘膜重塑，这是一种肠道适应的范例。我们将使用遗传和细胞相结合的方法来检验这样一个假设，即不同的系统和局部机制调节营养驱动的适应。目标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将研究全身性营养敏感内分泌信号，特别是胰岛素和果蝇神经肽Y同系物在动态平衡重建中的作用。目的3将通过确定肠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，最终在基因筛查中确定促进短期内稳控制的新基因，包括营养敏感和不敏感。这些研究的结果将为肠道适应的基础途径提供新的线索。在David Bilder博士的指导和John Forte博士的共同指导下，候选人将获得GI生理学、干细胞生物学和基因筛查等较新领域的专业知识，同时追求她对上皮组织动力学的长期兴趣。这项研究和培训计划将帮助候选人在加州大学伯克利分校分子和细胞生物学系内建立一个独立和互补的研究项目，从而促进她向自主能力的发展。 与公共卫生相关：肠道自我更新的能力可能会被伤害和疾病压倒，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，这是一个简单的动物模型，将产生新的线索，可以在哺乳动物身上进一步探索。

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.