Nutrition, ageing and prostate cancer: an experimental approach using Drosophila

营养和衰老生物学能解决前列腺癌问题吗？该项目将通过在果蝇身上的实验来验证这一观点。前列腺癌(PCA)占英国男性癌症的四分之一以上，其中三分之一发生在75年前。环境风险因素的证据是世界范围内PCA比率的差异和移民改变国家时风险的变化。在风险因素中，营养尤为重要。在分子水平上，它被认为与mTORC1营养感知通路中被错误调节的mTOR信号有关。不幸的是，这些机制如何在体内导致癌症，目前还不清楚，这限制了进展。营养和mTOR是已知的在进化上保守的衰老和年龄相关疾病的调节因子，mTOR在促进肿瘤的外切体产生中发挥作用。但营养/mTOR干预是否可以预防或逆转PCA仍不清楚。为了从实验上解决这个多维问题，我们建议使用功能遗传学的发电站--果蝇(Drophila Blackogaster)。博士的目标将是分析年龄和(1)饮食，(2)使用基因操作的mTORC1通路组件，以及(3)精确靶向mTORC1通路组件的药物对不同前列腺生长状态(良性、PCa和去势耐受前列腺癌[CRPC])的前列腺样细胞生长和基因组复制的影响。Fly系统允许在PCA模型中快速测试饮食、遗传和药物干预。雄性果蝇的次级细胞(SCs)与人类前列腺有共同的基本特征：它们制造精液和外体，生长受到类固醇依赖和非依赖信号的调节，分别反映了健康的前列腺和CRPC。干细胞的生长和内复制将在(A)雄性饲料中进行分析，其中包括碳水化合物、蛋白质和脂肪的不同组成，包括已知的延长寿命的成分；(B)具有影响mTORC1信号的突变的雄性，重点是那些已知的延长寿命的突变；以及(C)接受针对mTORC1途径成分的延长寿命药物的雄性，这项工作将解决整个动物系统中体内一个重要的健康问题的生物学复杂性。它将为未来新的或改进的干预措施提供机会，以预防或改善前列腺癌，作为更广泛的预防老龄化多病的一部分。

Can nutritional and ageing biology solve the problem of prostate cancer? This project will test this idea using experiments in Drosophila.Prostate cancer (PCa) accounts for more than a quarter of male cancers in the UK, one third of which occur >75yrs. Environmental risk factors are evidenced by worldwide variation in PCa rates and changes in risk when migrants change countries. Among risk factors, nutrition is of particular importance. At a molecular level, it is thought to be linked to mis-regulated mTOR signalling in the mTORC1 nutrient-sensing pathway. Unfortunately, there is little clarity on how these mechanisms connect to cause cancer in vivo, limiting progress. Nutrition and mTOR are known evolutionarily conserved regulators of ageing and age-related disease, and mTOR plays a role in tumour-promoting exosome production. But whether nutrient/mTOR interventions could prevent or reverse PCa remains unclear. To address this multidimensional problem experimentally, we propose to use the functional genetics powerhouse, the fruit fly (Drosophila melanogaster).The PhD's objectives will be to assay the impacts of age and (1) diet, (2) mTORC1 pathway components using genetic manipulations, and (3) drugs that precisely target components of the mTORC1 pathway, on prostate-like cell growth and genome replication in different prostate growth states (benign, PCa, and castration-resistant prostate cancer [CRPC]).The fly system allows for rapid tests of diet, genetic and pharmaceutical interventions in a PCa model. The secondary cells (SCs) of male Drosophila share fundamental features with the human prostate: they make seminal fluid and exosomes, and growth is regulated by steroid-dependent and -independent signals, mirroring healthy prostate and CRPC respectively. SC growth and endoreplication will be assayed in (A) males fed diets that vary in carbohydrates, protein, and fats, including compositions known to extend lifespan, (B) males with mutations affecting mTORC1 signalling, focusing on those known to extend lifespan, and males with SC-specific manipulation of mTORC1 signalling, and (C) males treated with lifespan-extending drugs that target mTORC1 pathway components.This work will address biological complexity of an important health problem in vivo in a whole animal system. It will provide opportunities for future novel or improved interventions, to prevent or ameliorate prostate cancer, as part of wider geroprotection against the multimorbidities of ageing.