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

本提案的总体目标是确定性腺类固醇激素和肠-脑轴相互作用并诱导规范应激和免疫反应性的年龄和性别差异的潜在机制。压力和免疫系统密切相关，并以双向方式交流。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。我的实验室和其他人已经证明，LPS暴露会引起年龄和性别特异性的应激和免疫反应。现有文献表明，青春期性腺类固醇激素启动HPA轴和免疫系统的成熟，促进应激和免疫反应性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轴发育的机制尚不清楚。肠道微生物组也通过肠-脑轴调节压力和免疫反应，但其潜在机制尚不清楚。因此，具体目标1将确定性腺激素的作用以及性腺功能的潜在遗传和表观遗传机制在调节小鼠急性外周和中枢应激和免疫反应的年龄和性别相关差异中的作用。然后，在具体目标2中，我们将研究性腺激素在调节脑血脑屏障通透性和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将研究肠脑轴在年龄和性别特异性应激和免疫反应中的作用。提出的目标建立在我之前的NSERC资助的研究项目的基础上，并在NSE中使用创新和变革的探究线，以显著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性的规范年龄和性别差异。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。这个研究项目还将为我的学员提供各种可转移的技术、实用和软技能，这些技能将有助于他们的职业定位。

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.