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: 10464925
• 负责人: Jordan Harris
• 金额: $ 3.42万
• 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/10464925
• 关键词: Acidity; Acne; Acne Vulgaris; Address; Antigens; Atopic Dermatitis; Bacteria; Biochemical; Biology; Cell Communication; Cells; Clinical Treatment; Collaborations; Communication Research; Cutaneous; Data; Dermatologist; Development; Disease; Engineering; Environment; Experimental Designs; Fatty Acids; Foundations; Future; Gene Expression; Generations; Germ-Free; Gland; Homeostasis; Hormones; Hydration status; Immune; Immune system; Infection; Infection prevention; Infectious Skin Diseases; Inflammatory; Knockout Mice; Lipids; Measures; Mediating; Mediator of activation protein; 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-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 皮脂为皮肤提供重要的功能，包括保湿和抵御外来入侵， 锡永。尽管皮脂具有明确的免疫功能，但免疫系统对皮脂在免疫系统中的作用的调节， 皮肤内稳态是未知的。皮脂腺（sebaceous glands，SG）是一种富含脂质的物质， 保持脂肪酸并诱导抗菌肽表达。皮脂分泌随着青春期的开始而增加 并且此后部分地由雄激素调节。皮脂分泌过多易患寻常痤疮， 而功能不全可破坏皮肤屏障功能，如在特应性皮炎中所见。目前的治疗方法 针对SGs可能是有害的，而且往往是无效的，因此迫切需要进一步研究， 皮脂分泌的介质，没有它的皮脂失调的临床治疗仍然缺乏。 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细胞生成素（TSLP）， 受体破坏皮脂分泌，信号传导通过T细胞发生，支持存在一种 免疫-皮脂调节回路。我们建议确定介导这种T细胞反应的激活信号 并启动免疫-皮脂调节。皮肤细菌群落促进组织特异性免疫 系统开发，包括产生组织驻留的微生物特异性T细胞。有可能皮肤 微生物组通过T细胞活化参与调节SG功能。事实上，初步结果表明， 无菌（GF）小鼠分泌的皮脂比对照少。这导致了一个总体假设，即皮肤微生物群 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 并作为一个重要的稳态先天防御皮肤感染。目标1涉及常规化 用GF小鼠皮肤微生物群与对照组比较，以确定皮肤微生物群进行适当 皮脂分泌转基因鼠模型将与经工程改造以表达卵清蛋白的细菌一起使用 抗原，以确定调节是否通过微生物特异性T细胞发生。在Aim 2中，TSLP受体敲除 将使用小鼠来确定在稳态时TSLP介导的皮脂分泌（1）是否促进皮肤屏障 功能通过测量经表皮水分流失，水合作用和pH值，和（2）防止感染的葡萄球菌， 金黄色葡萄球菌表皮感染模型。这项研究将形成一个基础，允许识别新的治疗， 用于与皮脂失调相关的常见皮肤病的治疗靶点。 为了完成这些实验，并进一步发展我作为一个物理学家，科学家，严格的 提出了培训计划，重点阐述了我的实验设计和实施的细化， 科学交流、研究合作和指导技能。本次培训将在联合国- 在宾夕法尼亚大学，我将继续提高我的科学研究和病人护理的整合 医学科学家培训计划提供的指导和编程。这是一个高度 创新和资源丰富的环境，我发展为未来的皮肤科医生，科学家。