Elucidating microbial and host mechanisms supporting early life immune imprinting by skin monocytes

阐明支持皮肤单核细胞早期生命免疫印记的微生物和宿主机制

• 批准号: 10283433
• 负责人: Miqdad Onali Dhariwala
• 金额: $ 8.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283433
• 关键词: Adult; Atopic Dermatitis; Automobile Driving; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; Cell physiology; Cells; Chemotaxis; Chronic; Cues; Cutaneous; Cytometry; Data; Development; Disease; Environment; Genetic; Gnotobiotic; Goals; Health; Health Promotion; Hidradenitis Suppurativa; Homeostasis; Human; Immune; Immune Tolerance; Immune system; Immunity; Immunology; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-17; International; Life; Link; Lymphocyte; Measures; Mentorship; Microbe; Microbiology; Molecular; Mus; Myelogenous; Myeloid Cells; Natural Immunity; Neonatal; Pathology; Pathway interactions; Phenotype; Play; Population; Positioning Attribute; Postdoctoral Fellow; Predisposition; Production; Psoriasis; Receptor Signaling; Recovery; Regulatory T-Lymphocyte; Research; Research Training; Role; Sentinel; Shapes; Signal Transduction; Skin; Skin Tissue; Systems Development; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Toll-like receptors; Training; Transgenic Mice; Translational Research; Work; career; chemokine; chronic inflammatory disease; chronic inflammatory skin; commensal bacteria; commensal microbes; comparative; early life exposure; high throughput screening; human tissue; humanized mouse; imprint; improved; in vivo; innovation; keratinocyte; metabolomics; microbial; microbial host; microorganism; monocyte; mouse model; neonatal human; neonate; next generation; novel; novel therapeutic intervention; programs; recruit; response; single-cell RNA sequencing; skin disorder; symbiont; symposium; tool; trafficking; translational study

PROJECT SUMMARY/ABSTRACT: Early life interactions between commensal microbes and the developing immune system have formative effects on human health and susceptibility to chronic inflammatory disease. Previous studies from the host lab and other groups have demonstrated that our microbial symbionts can tune skin-resident T cell function, especially during the neonatal window. However, comparatively little is known about how commensals influence cutaneous myeloid immunity in early life. Dr. Dhariwala has found that commensal microbes influence the composition and function of the myeloid compartment in neonatal skin. Specifically, commensal microbes drive the accumulation of a population of Ly6ChiMHC-IIlo inflammatory monocytes in neonatal skin. These cells have traditionally been studied as primary mediators of inflammation in response to infection or for their ability to fill vacant tissue myeloid niches. However, Dr. Dhariwala’s preliminary studies demonstrate a previously unexplored regulatory immune imprinting role for neonatal skin monocytes. To dissect the molecular mechanisms that underpin this phenomenon, we will employ a combination of transgenic mouse models, high throughput assays like mass cytometry and single cell RNA sequencing along with novel ex vivo translational tools. Studies proposed in this application will (Aim 1) Dissect the mechanism(s) by which commensal microbes influence monocyte recruitment and function in neonatal skin, (Aim 2) Elucidate the mechanism(s) by which neonatal monocytes contribute to skin immune homeostasis and (Aim 3) Functionally elucidate the role of neonatal monocytes in human skin. Results from this cross-disciplinary approach will benefit our understanding of early immune development and lay the groundwork for next generation therapies for chronic inflammatory diseases. The proposed research and training plan will build on Dr. Dhariwala’s strengths in the fields of microbiology, immunology and translational science. Leveraging tools he has established in the host lab, such as mass cytometry, ex vivo functional assays in human skin and manipulation of skin-resident myeloid cell populations in murine models, along with studies like metabolomics proposed in this application will not only elevate the project but also advance his training. His scientific and career progress will be well supported by a strong mentorship team including Drs. Tiffany Scharschmidt, Clifford Lowell, Michael Rosenblum and Peter Turnbaugh. Additionally, through presentations at local and international conferences along with formal and informal training at UCSF Dr. Dhariwala will advance his transition to independence. Promising preliminary data, a strong training plan and an excellent training environment will allow Dr. Dhariwala to carve out a niche for himself and establish an independent research program studying the influence of commensal microbes on myeloid immune development in neonatal barrier tissues.

项目总结/摘要： 在生命早期，肠道微生物和发育中的免疫系统之间的相互作用， 对人体健康和慢性炎症性疾病的易感性的影响。主机实验室的先前研究 和其他小组已经证明，我们的微生物共生体可以调节皮肤驻留T细胞的功能， 尤其是在新生儿期然而，相对而言，人们对这些人如何影响 早期皮肤髓系免疫。Dhariwala博士发现，肠道微生物会影响 新生儿皮肤中骨髓室的组成和功能。具体来说，肠道微生物 新生儿皮肤中Ly 6 ChiMHC-IIlo炎症单核细胞群体的积累。这些细胞具有 传统上被研究为响应感染的炎症的主要介质或其填充的能力， 空组织髓样龛。然而，Dhariwala博士的初步研究表明， 调节新生儿皮肤单核细胞的免疫印迹作用。来剖析 为了支持这一现象，我们将采用转基因小鼠模型、高通量检测 如质谱细胞术和单细胞RNA测序沿着新的离体翻译工具。研究 本申请中提出的方法将（目的1）剖析微生物影响微生物的机制， 新生儿皮肤中单核细胞的募集和功能，（目的2）阐明新生儿皮肤中单核细胞募集和功能的机制， 单核细胞有助于皮肤免疫稳态和（目的3）功能阐明新生儿的作用 单核细胞的数量。这种跨学科方法的结果将有助于我们了解早期 免疫发展，并为下一代慢性炎症性疾病的治疗奠定基础。 拟议的研究和培训计划将建立在Dhariwala博士在微生物学领域的优势之上， 免疫学和转化科学。利用他在主机实验室建立的工具，如质量 细胞术、人皮肤中的离体功能测定和人皮肤中的皮肤驻留骨髓细胞群的操作。 小鼠模型，沿着本申请中提出的代谢组学等研究， 而且还可以促进他的训练。他的科学和职业进步将得到强有力的指导的大力支持 团队成员包括Tiffany Scharschlem、Clifford Lowell、Michael Rosenblum和Peter Turnbaugh博士。 此外，通过沿着正式和非正式培训，在地方和国际会议上介绍情况 在UCSF，Dhariwala博士将推动他向独立的过渡。有希望的初步数据，强有力的培训 计划和良好的培训环境将使Dhariwala博士为自己开辟一个利基市场， 一个独立的研究项目，研究肠道微生物对骨髓免疫的影响， 新生儿屏障组织的发育。