The trigger and homeostatic function of a novel immune-sebum circuit

新型免疫皮脂回路的触发和稳态功能

• 批准号: 10662229
• 负责人: Jordan Harris
• 金额: $ 0.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10662229
• 关键词: Acidity; Acne; Acne Vulgaris; Address; Antigens; Atopic Dermatitis; Bacteria; Biochemical; Biology; Cell Communication; Cells; Clinical Treatment; Collaborations; Communication; Cutaneous; Data; Dermatologist; Development; Disease; Engineering; Environment; Experimental Designs; Fatty Acids; Foundations; Future; Gene Expression; Generations; Germ-Free; Growth; Homeostasis; Hormones; Hydration status; Immune; Immune system; Infection; Infection prevention; Infectious Skin Diseases; Inflammatory; Invaded; Knockout Mice; Laboratory Finding; Lipids; Measures; Mediating; Mediator; Medical; Mentorship; Microbe; Modeling; Molecular; Mus; Ovalbumin; Pathway interactions; Patient Care; Pennsylvania; Physicians; Predisposition; Production; Puberty; Regulation; Research; Resistance to infection; Resources; Role; Scientist; Sebaceous Glands; Sebum; Severities; Signal Transduction; Skin; Source; Specificity; Staphylococcus aureus; Staphylococcus epidermidis; Systems Development; T cell response; T-Cell Activation; T-Cell Immunologic Specificity; T-Lymphocyte; TSLP gene; Techniques; Testing; Tissues; Training; Training Programs; Transgenic Mice; Transgenic Organisms; Universities; Water; androgenic; antimicrobial peptide; bacterial community; commensal bacteria; cytokine; epithelial injury; experimental study; immune function; improved; in vivo; innovation; insight; keratinocyte; microbial; microbiota; mouse model; new therapeutic target; novel; overexpression; pathogen; receptor; skills; skin barrier; skin disorder; skin microbiome; skin microbiota; therapeutic target; therapeutically effective

PROJECT SUMMARY Sebum provides vital functions to the skin including moisture retention and defense against foreign inva- sion. Despite the well-defined immunologic function of sebum, immune system regulation of sebum’s role in cutaneous homeostasis is unknown. A lipid-rich substance produced in sebaceous glands (SGs), sebum con- tains fatty acids and induces antimicrobial peptide expression. Sebum secretion increases with puberty onset and is thereafter regulated in part by androgenic hormones. Sebum hypersecretion predisposes to acne vulgaris, whereas insufficiency could disrupt skin barrier function as seen in atopic dermatitis. As current therapeutics targeting SGs can be harmful and often ineffective, there is a critical need for further research into additional mediators of sebum secretion, without which clinical treatment of sebum dysregulation remains lacking. We have found that absence of the keratinocyte derived cytokine thymic stromal lymphopoietin (TSLP) receptor disrupts sebum secretion and that signaling occurs through T cells, supporting the existence of an immune-sebum regulatory circuit. We propose to identify the activating signal that mediates this T cell response and initiates immune-sebum regulation. Skin commensal bacterial communities promote tissue-specific immune system development, including generation of tissue-resident, microbial-specific T cells. It is possible that the skin microbiome is involved in regulating SG function through T cell activation. Indeed, preliminary results show that germ-free (GF) mice secrete less sebum than controls. This leads to the overall hypothesis that skin microbiota induces TSLP-mediated, microbial-specific T cell-dependent sebum secretion, promoting skin barrier function and acting as an important homeostatic innate defense against skin infection. Aim 1 involves conventionalizing GF mice with skin commensal bacteria from controls to determine the necessity of skin microbiota for appropriate sebum secretion. Transgenic murine models will be used with bacteria engineered to express an ovalbumin antigen to determine if regulation occurs through microbiota-specific T cells. In Aim 2, TSLP receptor knockout mice will be used to determine if, at homeostasis, TSLP-mediated sebum secretion (1) promotes skin barrier function by measuring transepidermal water loss, hydration and pH, and (2) prevents infection in a Staphylococ- cus aureus epidermal infection model. This research will form a foundation to allow identification of novel thera- peutic targets for common cutaneous conditions associated with sebum dysregulation. In order to complete these experiments and further my development as a physician-scientist, a rigorous training plan has been proposed focused on the refinement of my experimental design and implementation, scientific communication, research collaboration, and mentorship skills. This training will take place at the Uni- versity of Pennsylvania where I will continue to improve my integration of scientific research and patient care with the guidance and programming offered by the Medical Scientist Training Program. This presents a highly innovative and resource rich environment for me to develop as a future dermatologist-scientist.

项目摘要 皮脂为皮肤提供了重要功能，包括保留水分和防御外国人的侵害 锡。尽管皮脂具有明确定义的免疫功能，但皮脂中的免疫系统调节 皮肤稳态尚不清楚。皮脂腺（SGS），皮脂结合产生的富含脂质的物质 脂肪酸并诱导抗菌胡椒表达。皮脂分泌随着青春期发作而增加 此后，部分受雄激素调节。皮脂过度分泌易患痤疮， 而不足可能会破坏特应性皮炎中的皮肤屏障功能。作为当前的治疗学 针对SGS可能是有害的，而且通常无效，需要进一步研究进一步研究 皮脂分泌的介体，没有该临床治疗皮脂失调。 我们发现缺乏角质形成细胞衍生的细胞因子胸腺基质淋巴结蛋白（TSLP） 受体破坏皮脂分泌，并通过T细胞发生信号传导，支持存在 免疫隔离调节电路。我们建议确定介导该T细胞反应的激活信号 并启动免疫渗透调节。皮肤共生细菌群落促进组织特异性免疫 系统开发，包括生成组织居民微生物特异性T细胞。皮肤可能 微生物组参与通过T细胞激活来调节SG功能。确实，初步结果表明 无菌丝（GF）小鼠分泌皮脂比对照组少。这导致总体假设是皮肤菌群 诱导TSLP介导的微生物特异性T细胞依赖性皮脂分泌，促进皮肤屏障功能 并充当针对皮肤感染的重要稳态防御。 AIM 1涉及常规化 来自对照组的皮肤共生细菌的GF小鼠确定皮肤菌群的必要 皮脂分泌。转基因鼠模型将与经过工程的细菌一起使用以表达椭圆蛋白 抗原确定调节是否通过微生物群特异性T细胞发生。在AIM 2中，TSLP受体敲除 小鼠将用于确定在稳态，TSLP介导的皮脂分泌（1）是否促进皮肤屏障 通过测量跨皮皮肤流失，水合和pH的功能，以及（2）防止在葡萄球菌中感染 CUS金黄色表皮感染模型。这项研究将构成一个基础，允许识别新颖的thera- 与皮脂失调相关的常见皮肤状况的同性靶标。 为了完成这些实验，并进一步发展了我作为身体科学家的发展 培训计划已被提出，重点是我的实验设计和实施， 科学沟通，研究合作和心理技能。该培训将在Uni- 宾夕法尼亚州的版本，我将继续改善我的科学研究和患者护理的整合 在医学科学家培训计划提供的指导和编程中。这表现出很高的 创新和资源丰富的环境让我发展为未来的皮肤科医生科学家。