Mechanisms of age- and sex-specific stress and immune reactivity.

这项建议的总体目标是确定潜在的机制，通过性腺类固醇激素和肠-脑轴相互作用，并诱导年龄和性别差异的正常压力和免疫反应。压力和免疫系统是密切相关的，并以双向的方式进行沟通。脂多糖（LPS）是一种常见的实验室应激源，用于引发应激和免疫反应。我的实验室和其他实验室已经表明，LPS暴露会增加年龄和性别特异性应激和免疫反应。现有的文献表明，青春期性腺类固醇激素启动HPA轴和免疫系统的成熟，并促进应激和免疫反应性的性别差异的发展和表达。然而，性腺类固醇激素影响青春期HPA轴发育的机制仍然是难以捉摸的。肠道微生物组还通过肠-脑轴调节应激和免疫反应，但其潜在机制仍不清楚。因此，具体目标1将确定性腺性激素的作用和性腺功能的潜在遗传和表观遗传机制，在小鼠急性外周和中枢应激和免疫反应中调节年龄和性别相关差异。然后，在具体目标2中，我们将研究性腺性激素在调节血脑屏障通透性和脑中小胶质细胞功能的年龄和性别相关差异中的作用。最后，具体目标3将检查肠-脑轴在年龄和性别特异性应激和免疫反应中的作用。拟议的目标建立在我以前的NSERC资助的研究计划，并使用NSE的创新和变革性的调查线，以显着推进我们对内分泌和微生物因素的理解，这些因素会导致压力和免疫反应的正常年龄和性别差异。拟议研究计划产生的结果将适合向公众、利益相关者和研究界传播。这项研究计划还将为我的学员提供各种可转移的技术，实用和软技能，无论他们的职业方向如何，都将帮助他们。

The overarching objective of this proposal is to identify the potential mechanisms through which the gonadal steroid hormones and the gut-brain axis interact and induce age and sex differences in normative stress and immune reactivity. The stress and immune systems are intimately related and communicate in a bidirectional manner. Lipopolysaccharide (LPS) is a common laboratory stressor used to elicit both stress and immune responses. My laboratory and others have shown that LPS exposure elicits age and sex-specific stress and immune responses. The existing literature suggests that pubertal gonadal steroid hormones initiate the maturation of the HPA axis and of the immune system and facilitate the development and expression of sex differences in stress and immune reactivity. However, the mechanisms through which gonadal steroid hormones influence the development of the HPA axis during puberty remain elusive. The gut microbiome also regulates stress and immune responses through the gut-brain axis, but the underlying mechanisms are still unclear. Therefore, specific objective 1 will identify the role of gonadal sex hormones and the underlying genetic and epigenetic mechanisms of gonadal function in the modulation of age- and sex-related differences in acute peripheral and central stress and immune responses in mice. Then, in specific objective 2, we will investigate the role of gonadal sex hormones in the modulation of age- and sex-related differences in blood-brain barrier permeability and microglial function in the brain. Finally, specific objective 3 will examine the role of the gut-brain axis in the age- and sex-specific stress and immune responses. The proposed objectives build on my previous NSERC funded research program and use an innovative and transformative line of inquiry in the NSE to significantly advance our understanding of the endocrine and microbial factors that induce normative age and sex differences in stress and immune reactivity. The results generated by the proposed research program will be suitable for dissemination to the public, stakeholders and research community. This research program will also provide my trainees with a variety of transferable technical, practical and soft skills that will help them regardless of their career orientation.