Role of perinatal androgens on the development of the sexually dimorphic mast cell

围产期雄激素对性二态性肥大细胞发育的作用

• 批准号: 9902568
• 负责人: Emily Mackey
• 金额: $ 3.2万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902568
• 关键词: Adult; Anaphylaxis; Androgen Receptor; Androgenization; Androgens; Animal Model; Animals; Applications Grants; Autoimmune Diseases; Biological Response Modifiers; Bone Marrow; Cells; Characteristics; Child; Childhood; Clinical; Cytoplasmic Granules; Data; Development; Disease; Disease susceptibility; Effector Cell; Elderly; Estrogens; Estrous Cycle; Exhibits; Family suidae; Female; Functional disorder; Future; Gastrointestinal Diseases; Gene Expression Profile; Genetic Transcription; Germ Cells; Goals; Gonadal Steroid Hormones; Hematopoietic; Histamine; Human; Hypersensitivity; IgE; Immune; Immune System Diseases; Immune response; Immunologics; Irritable Bowel Syndrome; Life; Mediating; Mediator of activation protein; Mentors; Migraine; Modeling; Mus; Outcome; Peptide Hydrolases; Perinatal; Phenotype; Play; Positioning Attribute; Predisposition; Psychological Stress; Puberty; Publishing; RNA; Rattus; Research; Research Project Grants; Risk; Risk Factors; Rodent Model; Role; Scientist; Serotonin; Sex Bias; Sex Differences; Stress; Testing; Training; Work; androgen sensitive; base; biological sex; chronic pain; chronic painful condition; design; experimental study; male; mast cell; mastocytosis; mutant; novel; novel therapeutics; perinatal period; prepuberty; prevent; psychological stressor; public health relevance; resilience; response; sex; sexual dimorphism; stem cells; transcriptome

PROJECT SUMMARY A major risk factor in the vulnerability to immune disorders is biological sex. In some of the most prevalent immune disorders such as allergy/anaphylaxis, autoimmune disease, and chronic pain disorders, females are at increased risk. Adult sex hormones, such as estrogen, may explain some of the sex differences; however, this is challenged by the fact that many immune disorders exhibit a sex bias in prepubertal children. Our recent published and preliminary studies have uncovered sex differences in the mast cell that may explain female vulnerability or male resilience to many immune disorders. Mast cells are innate immune cells that act as effector cells and orchestrators of the immune response. The fact that many mast cell-associated disorders (allergy, autoimmune disease, chronic pain disorders, irritable bowel syndrome) exhibit a sex bias in both childhood and adulthood positions the mast cell as a novel regulator of sex differences in immune diseases. Specifically, we have shown that female mast cells possess an increased capacity to synthesize, store and release potent mast cell mediators including histamine, serotonin, proteases, etc. In animal models of IgE- mediated anaphylaxis and psychological stress, female animals exhibited enhanced release of mast cell mediators and more severe pathophysiologic and clinical disease, similar to findings in humans. Moreover, our recent preliminary data demonstrates that sex differences in mast cells emerge early in life prior to puberty and thus may explain sex differences observed in children. The components of sexual differentiation that impact the mast cell phenotype and consequently increase female vulnerability to immune disorders is unknown. Based on preliminary data, we hypothesize that sex differences in mast cell phenotype and immune-related disease susceptibility are established early in life by perinatal androgens. In this F30 proposal, we aim to establish the role of perinatal androgens in determining sex differences in the mast cell and susceptibility/resiliency to later life immune pathophysiology in immunological and psychological stress models. Toward this goal, by conducting perinatal androgenization experiments in mice we will 1) identify the contribution of perinatal androgens in mast cell disease susceptibility and 2) determine the contribution of perinatal androgens in mast cell phenotype, function, and gene expression patterns. The exploratory studies proposed in the grant application will represent a major paradigm shift in the understanding of sex and mast cell-related immune disorders.

项目摘要 易患免疫系统疾病的一个主要危险因素是生理性别。在一些最流行的 免疫疾病如变态反应/过敏性反应、自身免疫疾病和慢性疼痛疾病， 风险更大成年人的性激素，如雌激素，可以解释一些性别差异;然而， 这一点受到以下事实的挑战，即许多免疫疾病在青春期前儿童中表现出性别偏见。我们最近 已发表的和初步的研究揭示了肥大细胞的性别差异，这可能解释了女性 脆弱性或男性对许多免疫系统疾病的适应力。肥大细胞是先天免疫细胞， 效应细胞和免疫反应的协调。事实上，许多肥大细胞相关疾病 （过敏症、自身免疫性疾病、慢性疼痛障碍、肠易激综合征）在这两个方面都表现出性别偏见。 儿童期和成年期定位肥大细胞作为一种新的调节免疫疾病的性别差异。 具体来说，我们已经表明，女性肥大细胞具有增加的能力，合成，储存， 释放有效的肥大细胞介质，包括组胺、血清素、蛋白酶等。 介导的过敏反应和心理应激，雌性动物表现出肥大细胞释放增强 介质和更严重的病理生理和临床疾病，类似于人类的发现。而且我们 最近的初步数据表明，肥大细胞的性别差异出现在青春期之前的生命早期， 这可以解释在儿童中观察到的性别差异。影响性别差异的因素 肥大细胞表型和因此增加的女性对免疫紊乱的脆弱性是未知的。 基于初步数据，我们假设肥大细胞表型和免疫相关性的性别差异 疾病易感性在生命早期由围产期雄激素确定。在这份F30提案中，我们的目标是 确定围产期雄激素在决定肥大细胞性别差异中的作用， 在免疫学和心理应激模型中对晚年免疫病理生理学的易感性/弹性。 为了实现这一目标，通过在小鼠中进行围产期雄激素化实验，我们将：1）确定 围产期雄激素在肥大细胞疾病易感性中的作用; 2）确定 围产期雄激素对肥大细胞表型、功能和基因表达模式的影响。探索性研究 在补助金申请中提出的将代表对性和肥大的理解的重大范式转变， 细胞相关的免疫紊乱