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

基本信息

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
项目类别：
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

项目摘要

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.