Regulation of intestinal stem cell behavior by occluding junctions

项目摘要 皮肤、肝脏、血液和肌肉等组织的维持和再生能力急剧下降， 然而，能够协调组织和有机体衰老的分子机制还没有 被阐明。此外，还不知道一种组织的功能是否比其他组织更重要 in influencing影响healthspan健康and lifetime长寿.衰老导致肠道屏障功能丧失 从苍蝇到人类;然而，老年人对肠道功能障碍的脆弱性增加并不是 完全理解在这里，我们建议开发果蝇消化道作为一个模型来研究 构成肠屏障的复合物与肠干细胞的关系 (ISC)行为，以及与年龄相关的肠道屏障功能丧失的机制。 肠上皮提供了允许营养物和水运输的选择性屏障， 防止吸收有害的环境毒素和间质组织的微生物污染。在 除了屏障功能外，肠上皮细胞还具有基本的代谢和先天免疫功能， 功能协调发展的在哺乳动物中，肠屏障功能的丧失和肠通透性的增加与 细胞-细胞连接的完整性受损，称为紧密连接（TJ）。分隔连接（SJS）， 脊椎动物TJ的果蝇类似物，对于调节顶端和基底之间的细胞旁流是重要的 上皮表面果蝇肠道中的SJ组分尚未完全表征，其 在整个老化过程中维持肠完整性的潜在作用尚未被研究。我们的初步 数据表明，SJ组分的表达和定位存在与年龄相关的变化， 果蝇后中肠例如，我们在三细胞连接（TCJ）处发现了改变， 三/四个细胞会聚的特殊结构，以及几个SJ的细胞质积累 件.因此，我们假设SJ/TCJ功能随年龄的丧失导致ISC的快速变化， 行为，这有助于老年动物肠道内稳态的丧失。我们将直接通过 以下具体目标： 1)描述TCJ在调节ISC行为和肠道老化表型中的作用 2)评估双细胞SJ在调节ISC行为和肠道老化表型中的作用 3)探讨神经胶质细胞（Nrg）在果蝇肠道中的作用 ISC增殖增加、肠道完整性丧失、代谢缺陷， 增加的炎症和生态失调是未知的。在这里，我们建议调查与年龄有关的变化， 作为近端事件，导致ISC行为的变化，并最终导致 组织内稳态我们的发现将对胃肠疾病的治疗产生重大影响 以及疾病、慢性炎症和癌症，特别是在老年人中。

Project Summary Maintenance and regeneration of tissues such as skin, liver, blood, and muscle decrease dramatically with age; however, molecular mechanisms that could serve to coordinate tissue and organismal aging have not been elucidated. Furthermore, it is not known whether the function of one tissue is more important than others in influencing healthspan and longevity. Aging results in loss of intestinal barrier function in species ranging from flies to humans; however, the increase in vulnerability to intestinal dysfunction in older individuals is not fully understood. Here we propose to develop the Drosophila melanogaster digestive tract as a model to study the relationship between the complexes that constitute the intestinal barrier and intestinal stem cell (ISC) behavior, as well as mechanisms underlying the age-related loss of intestinal barrier function. The intestinal epithelium provides a selective barrier that permits nutrient and water transport, while preventing uptake of harmful environmental toxins and microbial contamination of interstitial tissues. In addition to its barrier function, the intestinal epithelium also serves essential metabolic and innate immune functions. In mammals, loss of intestinal barrier function and increased intestinal permeability correlates with compromised integrity of cell-cell junctions, known as tight junctions (TJs). Septate junctions (SJs), the Drosophila analog of vertebrate TJs, are important for regulating paracellular flow between apical and basal epithelial surfaces. The SJ components in the Drosophila intestine have not been fully characterized, and their potential role in maintaining intestinal integrity throughout aging has not been interrogated. Our preliminary data indicate that there are age-related changes in the expression and localization of SJ components in the Drosophila posterior midgut. For example, we find alterations at tricellular junctions (TCJ), specialized structures where three/four cells converge, as well as cytoplasmic accumulation of several SJ components. Therefore, we hypothesize that loss of SJ/TCJ function with age leads to rapid changes in ISC behavior, which contribute to loss of intestinal homeostasis in older animals. We will test this directly through the following Specific Aims: 1) To characterize the role of TCJ in regulating ISC behavior and intestinal aging phenotypes 2) To assess the role of bicellular SJ in regulating ISC behavior and intestinal aging phenotypes 3) To explore the role of Neuroglian (Nrg) in the Drosophila intestine The causal relationships between increased ISC proliferation, loss of intestinal integrity, metabolic defects, increased inflammation, and dysbiosis are not known. Here we propose to investigate age-related changes in occulding junctions as a proximal event, leading to changes in ISC behavior and, ultimately, loss of tissue homeostasis. Our findings will have major implications for the treatment of gasterointestinal diseases and disorders, chronic inflammation, and cancer, particularly in older individuals.