Interplay of androgens, microbiota and immunoregulation in lupus

狼疮中雄激素、微生物群和免疫调节的相互作用

基本信息

批准号：
9330062
负责人：
MICHELE M KOSIEWICZ
金额：
$ 43.19万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330062
关键词：
Address Affect Agonist Androgen Receptor Androgens Autoimmune Diseases Castration Cell physiology Complex Cytoprotection Data Defect Dendritic Cells Development Diabetes Mellitus Disease Environment Estrogens Exhibits Feces Female Gonadal Steroid Hormones Health Human Immune response Immune system Immunologics In Vitro Inbred NOD Mice Incidence Inflammatory Insulin-Dependent Diabetes Mellitus Intestines Knowledge Lead Link Lupus Mediating Men&apos s Role Microbiological Techniques Modeling Mus Pathogenesis Phytol Play Prevention strategy Production Property Puberty RXR Receptor Signaling Regulatory T-Lymphocyte Role Severity of illness Symbiosis Systemic Lupus Erythematosus Techniques Therapeutic Treatment Protocols Tretinoin Volatile Fatty Acids Woman autoreactivity base commensal microbes disorder prevention fecal transplantation gender difference gut microbiota immunoregulation imprint in vivo innovation male men metabolome metabolomics microbiota mortality mouse model next generation sequencing novel novel therapeutics public health relevance sex

项目摘要

DESCRIPTION (provided by applicant): Resubmission Systemic lupus erythematosus (SLE) is much more prevalent in females than males in humans, and in the (NZBxNZW)F1 (BWF1) mouse model of lupus. Although estrogens can exacerbate disease in females, considerable evidence suggests that androgens play a critical role in protecting males from lupus in both humans and mice. The gut microbiota is now thought to play a major role in host health and disease, and microbiota dysbiosis is associated with development of autoimmune diseases. Interestingly, androgens can have a significant impact on the microbiota and vice versa. Recent studies in a mouse model of type 1 diabetes (T1D) suggest that the microbiota and androgens collaborate, in what is now being referred to as the "microgenderome", to protect male mice from disease via currently unknown mechanisms. However, little is known about the relationship between androgens and the microbiota in lupus. In preliminary studies, we have found that both the microbiota composition and metabolomic profile differ significantly between mature female and male BWF1 mice, and transfer of male microbiota to female BWF1 mice protects female recipients from disease, and significantly enhances survival. These data suggest that the male environment confers protective properties on the microbiota by altering microbiota composition and/or metabolome. Metabolites from commensal bacteria have been found to induce Treg differentiation both directly and through DC. The gut CD103+ dendritic cells (CD103DC) are highly tolerogenic, and generate regulatory T cells in the periphery that can control systemic immune responses. Our preliminary data showing sex-based differences in CD103DC function, and the requirement for CD103+ cells for protection in male BWF1 mice strongly support the notion that CD103DC function as a critical link between the male gut microbiota and the immune response, and may, therefore, play an important role in protecting BWF1 male mice from disease. Moreover, preliminary analysis of the microbiota metabolome has identified a metabolite that is increased in male BWF1 mice that may have an impact CD103DC function. We, therefore, hypothesize that the androgen-modified male microbiota and its metabolites protect against lupus by acting through the gut CD103DC. This novel hypothesis will be addressed in lupus-prone BWF1 mice by 1) examining the impact of androgens on the gut microbiota and its metabolites; 2) exploring the role of male microbiota and its metabolites in protection from disease; and 3) determining the role that CD103DC play in male microbiota- mediated protection from disease. The proposed project will fill the gaps in our knowledge about the role of the androgen-gut microbiota relationship in immunoregulation and lupus, and will lead to the development of novel therapeutic strategies using the microbiota and/or its metabolites for the treatment of lupus and other autoimmune diseases.

描述（由申请人证明）：重新提出系统性的红斑鱼（SLE）在人类中更为普遍。现在，在人类和小鼠中保护狼疮的角色在宿主健康和疾病中。。狼疮中的雄性生物群和雄性bwf1小鼠的转移可击败冰，并通过改变微生物群的特性，从而显着增强了疾病。直接通过DC进行区分。在雄性BWF1小鼠中，CD103DC充当雄性肠道微生物群弹药的关键联系，因此，在保护BWF1雄性小鼠免受疾病的影响方面可能起重要作用。在雄性BWF1小鼠中，可能会在lupus cd103dc中探索雄激素改性的雄性微生物ATS代谢物来防止狼疮的雄性微生物ATS代谢物。 2）LE Microbiota及其在保护疾病中的代谢物；它的代谢物用于治疗狼疮和其他自身免疫性疾病。