Exploring physiological impacts for bioactive lipids on mucosal immune functions during aging

探索衰老过程中生物活性脂质对粘膜免疫功能的生理影响

• 批准号: 2439757
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2439757
• 关键词: Exploring; physiological; impacts; bioactive; lipids

Aging is a series of processes with time-dependent deteriorative functional changes of organs, leading to a progressive disability of the organism in response to both internal and environmental stresses. Senescence-associated changes of immune responses in the respiratory tract play important roles in dysfunction of 'normal' aging epithelium (e.g. lung, gut) and the genesis of chronic lung/bowel diseases such as chronic obstructive pulmonary disease, IBD and bowel cancer. With increased life expectancy, a thoroughly advanced understanding how the epithelium undergoes physiological and immunological changes with age is needed for the success of public health programmes.Bioactive lipid mediators play critical roles in maintaining body homeostasis and have divergent effects in response to internal (e.g. age-relate genetic alterations) and external (e.g. life style, smoking, exposure to pollution, etc) influences. Prostaglandins (PGs), especially PGE2, are important lipid mediators which are produced in homeostatic tissues at physiological levels. PGE2 exerts its biological actions through binding to its receptors termed EP1-EP4. While engagement of EP2 and EP4 results in activation of cAMP signalling, EP1 and EP3 couple to activate calcium signalling and down-regulate cAMP signalling, respectively. PGE2 regulates many physiological processes, e.g. it mediates the pain response, fever generation (via EP3) and stress behaviour, fertilization facilitation, bone formation and other important processes. We and others have recently defined that PGE2 has profound impact on regulating both tissue resident and systemic immune responses. For example, PGE2 regulates effector T cell responses to environmental antigen stimulation and gut innate immune homeostasis (refs 1,2). During the process of aging, levels of PGE2 are altered in most tissues including the lung and gut, which is inversely correlated with the progressing dysfunction of tissue homeostasis and dysfunction of organs.In this PhD project we propose to study how bioactive lipid mediators are changed and how these changes modulate epithelial immune responses by focusing on adaptive and innate lymphocytes during physiological aging. We will employ cutting-edge immunological, physiological and genetic approaches to investigate the link between the lipid pathways and aging-associated lung immune dysfunction. We will also integrate the analysis of genome-wide gene expression data (e.g. microarray or RNA-sequence) and lipidomic data (e.g. arachidonic acid metabolites) to address the links among lipid mediators, transcriptomic networks and lung immune phenotypic traits in the normal aging process. Success in this project will help us to improve the understanding of the biology for immunological senescence, to ameliorate the negative consequences of advanced age, and to promote human health.

衰老是器官功能随时间变化的一系列过程，导致机体对内部和环境应激反应的进行性残疾。与衰老相关的呼吸道免疫反应的改变在“正常”衰老上皮(如肺、肠道)的功能障碍以及慢性阻塞性肺疾病、IBD和肠癌等慢性肺/肠疾病的发生中起着重要作用。随着预期寿命的延长，公共卫生计划的成功需要深入了解上皮细胞如何随着年龄发生生理和免疫变化。生物活性脂质介体在维持身体动态平衡方面发挥关键作用，并对内部(如与年龄相关的基因改变)和外部(如生活方式、吸烟、暴露于污染等)的影响具有不同的影响。前列腺素(PGs)，尤其是前列腺素E_2(PGE_2)是重要的脂质介质，在生理水平上产生于体内平衡组织。PGE2通过与其受体EP1-EP4结合而发挥其生物学作用。EP2和EP4的结合导致cAMP信号的激活，而EP1和EP3分别偶联激活钙信号和下调cAMP信号。PGE2调节许多生理过程，例如，它调节疼痛反应、发烧(通过EP3)和应激行为、促进受精、骨形成等重要过程。我们和其他人最近确定PGE2对调节组织驻留和全身免疫反应都有深远的影响。例如，PGE2调节效应器T细胞对环境抗原刺激和肠道天然免疫稳态的反应(参考文献1，2)。在衰老的过程中，包括肺和肠道在内的大多数组织中PGE2的水平都发生了变化，这与组织内稳态和器官功能的进行性失调呈负相关。在这个博士项目中，我们建议研究生物活性脂质介质是如何变化的，以及这些变化是如何通过关注适应性和先天淋巴细胞在生理衰老过程中调节上皮免疫反应的。我们将使用前沿的免疫学、生理学和遗传学方法来研究脂质途径和衰老相关的肺免疫功能障碍之间的联系。我们还将整合全基因组基因表达数据(例如微阵列或RNA序列)和脂组数据(例如花生四烯酸代谢物)的分析，以解决正常衰老过程中脂质介体、转录网络和肺免疫表型特征之间的联系。该项目的成功将有助于我们提高对免疫衰老生物学的认识，改善老年带来的负面后果，促进人类健康。