Sex differences in response to an immune challenge

对免疫挑战的反应存在性别差异

• 批准号: RGPIN-2014-05570
• 负责人: Ismail, Nafissa
• 金额: $ 2.84万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611715
• 关键词: Sex; differences; response; immune; challenge

Puberty is a critical period of development during which gonadal hormones reorganize and remodel the brain and set the stage for long-term brain functioning. Puberty is also a period during which the stress response is altered and exposure to stressors during puberty can disrupt normal brain development and exert lasting behavioural effects in adulthood. For example, pubertal (six weeks old) female mice exposed to shipping stress display enduring decreases in sexual receptivity compared to females shipped younger or older, even after complete hormonal priming with estradiol and progesterone. Since shipping is a multifactor variable stressor, a search for a controlled laboratory stressor showed that standard laboratories stressors, known to activate the stress response, all failed to replicate the effect of shipping on the enduring decrease in sexual receptivity, expect for one. Like shipping, intraperitoneal injection of lipopolysaccharide (LPS) causes long-lasting decreases in sexual receptivity in six-week old mice compared to controls. This effect is not present in younger or older mice. The enduring effect of pubertal LPS injection also extends to non-reproductive behaviours and affects cognitive and emotional functioning. These findings show that pubertal LPS treatment globally alters behaviors that are gonadal hormone-dependant. However, the mechanism through which pubertal immune challenge causes these behavioral changes remains to be investigated. There are several possible explanations for these findings. One possibility is that gonadal steroid hormones potentiate immune response during puberty, but this remains to be investigated. The work mentioned above on the effects of pubertal immune challenge was carried out solely in female mice, it would be important to also look for differences in immune response between pubertal and adult males as well, since it is well known that results in one sex do not readily translate to the other sex. Preliminary findings from my laboratory suggest that there are age and sex differences in sickness behavior following LPS treatment. The long-term vision of my research program is to identify the potential mechanisms through which pubertal immune challenge causes long-term alterations in gonadal hormone-dependent behavior. The short-term objectives of the proposed research program are to use an original and multidisciplinary approach to first characterize the age- and sex-related differences in acute immune response in mice. Second, I will examine the role of gonadal hormones and the underlying genetic and epigenetic mechanisms of gonadal function in the age and sex differences in the acute response to an immune challenge. Lastly, I will examine the role of experience and pubertal maturation on long-term immune response and stress reactivity. The idea that exposure to an immune challenge during puberty can permanently alter the response to gonadal hormones is a new and original concept and little is known about the mediating mechanisms. The proposed research program uses a multidisciplinary approach to characterize age- and sex-related differences in immune response and the effect of gonadal hormones in the vulnerability of the pubertal period to immune challenge. This research program will also show whether pubertal exposure to an immune challenge exerts long-term alterations to stress and immune responses. This work will expand the investigation of the basic mechanisms through which exposure to stressors shapes the developing brain and causes long-lasting alterations on the structure and function of the nervous system during sensitive periods of development by examining the interactions between the neuroendocrine, stress and immune systems during the pubertal period.

青春期是发育的关键时期，在此期间，性腺激素重组和重塑大脑，并为长期的大脑功能奠定基础。青春期也是压力反应发生改变的时期，青春期暴露于压力源会破坏正常的大脑发育，并对成年期产生持久的行为影响。例如，暴露于运输应激的青春期（6周龄）雌性小鼠与更年轻或更年长的运输雌性小鼠相比，即使在雌二醇和孕酮的完全激素引发后，也显示出性接受性的持久降低。由于航运是一个多因素变量的压力源，一个受控的实验室压力源的搜索表明，标准的实验室压力源，已知激活的压力反应，都未能复制航运的影响持久性降低性接受性，除了一个。与运输一样，与对照组相比，腹腔内注射脂多糖（LPS）会导致6周龄小鼠性感受性的长期下降。这种效应在年轻或年老的小鼠中不存在。青春期LPS注射的持久影响也延伸到非生殖行为，并影响认知和情感功能。这些研究结果表明，青春期LPS治疗在全球范围内改变了性腺激素依赖的行为。然而，青春期免疫攻击导致这些行为变化的机制仍有待研究。这些发现有几种可能的解释。一种可能性是性腺类固醇激素在青春期增强免疫反应，但这仍有待研究。上述关于青春期免疫激发影响的工作仅在雌性小鼠中进行，同样重要的是寻找青春期和成年雄性之间的免疫应答差异，因为众所周知，一种性别的结果不容易转化为另一种性别。从我的实验室的初步研究结果表明，有年龄和性别差异的疾病行为后LPS治疗。我的研究计划的长期愿景是确定青春期免疫挑战导致性腺依赖性行为长期改变的潜在机制。拟议研究计划的短期目标是使用原始和多学科的方法，首先表征小鼠急性免疫反应中与年龄和性别相关的差异。其次，我将研究性腺激素的作用和潜在的遗传和表观遗传机制的性腺功能的年龄和性别差异的急性反应的免疫挑战。最后，我将研究经验和青春期成熟对长期免疫反应和应激反应的作用。在青春期暴露于免疫挑战可以永久地改变对性腺激素的反应的想法是一个新的和原始的概念，并且对介导机制知之甚少。拟议的研究计划使用多学科的方法来表征年龄和性别相关的免疫反应的差异和性腺激素在青春期免疫挑战的脆弱性的影响。这项研究计划还将显示青春期暴露于免疫挑战是否会对压力和免疫反应产生长期改变。这项工作将通过研究青春期神经内分泌、压力和免疫系统之间的相互作用，扩大对基本机制的调查，通过这种机制，暴露于压力源塑造发育中的大脑，并在发育的敏感时期对神经系统的结构和功能造成长期的改变。