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.

项目概要 皮脂为皮肤提供重要功能，包括保湿和防御外来入侵。 尽管皮脂具有明确的免疫功能，但免疫系统对皮脂的调节作用。 皮脂腺（SG）中产生的一种富含脂质的物质，即皮脂，尚不清楚。 含有脂肪酸并诱导抗菌肽表达，随着青春期的开始而增加。 此后部分受到雄激素的调节，皮脂分泌过多易患寻常痤疮， 而不足可能会破坏皮肤屏障功能，如特应性皮炎中所见。 针对 SG 可能是有害的，而且往往无效，因此迫切需要进一步研究更多 皮脂分泌介质，如果没有它，皮脂失调的临床治疗仍然缺乏。 我们发现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）的缺失 受体破坏皮脂分泌，信号通过 T 细胞发生，支持了 我们建议鉴定介导这种 T 细胞反应的激活信号。 并启动免疫皮脂调节。皮肤共生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、微生物特异性的 T 细胞。 事实上，初步结果表明，微生物组通过 T 细胞激活参与调节 SG 功能。 无菌（GF）小鼠比对照组分泌更少的皮脂，这导致了皮肤微生物群的总体假设。 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 作为对抗皮肤感染的重要稳态先天防御，目标 1 涉及常规化。 GF 小鼠与对照组的皮肤共生细菌一起确定皮肤微生物群的必要性 转基因小鼠模型将与工程化表达卵清蛋白的细菌一起使用。 目标 2：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 通过测量经皮失水、水合作用和 pH 值发挥功能，并且 (2) 预防葡萄球菌感染 金黄色葡萄球菌表皮感染模型。这项研究将为鉴定新的治疗方法奠定基础。 与皮脂失调相关的常见皮肤病的治疗目标。 为了完成这些实验并进一步发展我作为一名医师科学家，严格的 已提出培训计划，重点是我的实验设计和实施的细化， 该培训将在大学进行，包括科学交流、研究合作和指导技能。 宾夕法尼亚大学，我将在那里继续提高科学研究和患者护理的融合 在医学科学家培训计划提供的指导和规划下，这提出了高度的要求。 创新和资源丰富的环境让我能够发展成为未来的皮肤科医生科学家。