Regulation of dietary polyamine uptake in Drosophila melanogaster

饮食中的多胺促进动物的健康衰老和长寿。因此，人们不得不假设肠道多胺摄取对于观察到的效果是至关重要的。然而，后生动物多胺转运的分子水平仍在争论中。在这里，模式生物果蝇黑腹果蝇将被用来鉴定参与食物多胺摄取的转运蛋白(S)，并阐明它们在多胺稳态、健康衰老以及相关表型(如肠道免疫敏感性和肿瘤发生)中的作用。为此，我们将结合果蝇强大的遗传工具箱，这是一种最近建立的神圣培养基，允许在无多胺和定义的多胺补充条件下生长和果蝇细胞培养。调节蛋白抗酶可能是多胺摄取的抑制因子。Antisyme的特征是一种独特的进化保守的+1移码机制，该机制控制着翻译过程。以多胺依赖的方式。通过利用转基因策略，将在体内系统地研究黑腹果蝇抗酶的表达调控，重点是在促进长寿的条件下，如增加饲料中的多胺水平，剥夺饲料中的氨基酸和减少mTOR信号转导。在此背景下，我们将揭开黑腹果蝇抗酶在饮食多胺摄取和衰老过程中的作用。饮食中多胺的有益作用可能(部分)由肠道微生物区系的改变引起。我们将采用诺生菌的方法来研究黑腹毛虫的这一问题。后生动物的多胺代谢很保守。因此，我们的研究很可能有助于更好地了解包括人类在内的其他生物对饮食中多胺的肠道摄取过程，这将对药理学和老年学研究产生影响。

Dietary polyamines promote healthy ageing and longevity in animals. Accordingly, one has to assume that the intestinal polyamine uptake is critical for the observed effects. However, the molecular level of metazoan polyamine transport is still under debate. Here, the model organism Drosophila melanogaster will be used to identify transporter(s) involved in the uptake of dietary polyamines and to elucidate their role in polyamine homeostasis, healthy ageing and related phenotypes such as intestinal immunosenecence and tumorigenesis. To this end, we will combine the powerful genetic tool box of the fruit fly, a recently established holidic medium that allows the growth under polyamine-free and defined polyamine supplementation conditions and Drosophila cell culture. The regulatory protein antizyme is a putative inhibitor of polyamine uptake. Antizymes are characterized by a unique evolutionary conserved +1 frameshifting mechanism that controls the translational process i.a. in a polyamine-dependent manner. By using transgenic strategies, the expression control of D. melanogaster antizyme will be systematically investigated in vivo focusing on longevity-promoting conditions such as increased dietary polyamine levels, dietary amino acid deprivation and reduced mTOR signaling. In this context, we will unravel the role of D. melanogaster antizyme in the uptake of dietary polyamines and the ageing process. The beneficial effects of dietary polyamines may be (partly) elicited by alterations in the intestinal microbiota. A gnotobiotic approach will be employed to examine this issue in D. melanogaster. The metazoan polyamine metabolism is well conserved. Hence, our studies will most probably lead to a better understanding of the intestinal uptake process of dietary polyamines in other organisms including humans with impact on pharmacological and geriatric research.