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.

项目摘要/摘要： 共生微生物与发育中的免疫系统之间的早期生命相互作用具有形成性 宿主实验室先前的研究对人类健康和对慢性炎症疾病的易感性的影响。 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 细胞功能， 特别是在新生儿窗口期间，然而，人们对共生体如何影响知之甚少。 Dhariwala 博士发现，共生微生物会影响生命早期的皮肤骨髓免疫。 具体而言，共生微生物驱动新生儿皮肤中骨髓室的组成和功能。 Ly6ChiMHC-IIlo 炎症单核细胞群在新生儿皮肤中积聚。 传统上被研究为响应感染或填充能力的炎症的主要介质 然而，Dhariwala 博士的初步研究表明，存在一个以前未曾探索过的组织。 新生儿皮肤单核细胞的调节性免疫印记作用剖析其分子机制。 为了支持这一现象，我们将结合使用转基因小鼠模型、高通量检测 例如质谱流式分析和单细胞 RNA 测序以及新颖的离体翻译工具。 本申请中提出的将（目标 1）剖析共生微生物影响的机制 新生儿皮肤中单核细胞的募集和功能，（目标 2）阐明新生儿皮肤中单核细胞的募集和功能的机制 单核细胞有助于皮肤免疫稳态，并且（目标 3）从功能上阐明新生儿的作用 这种跨学科方法的结果将有助于我们了解早期的单核细胞。 免疫发育并为下一代慢性炎症性疾病疗法奠定基础。 拟议的研究和培训计划将建立在 Dhariwala 博士在微生物学、 利用他在宿主实验室建立的工具，例如质量。 细胞计数、人体皮肤离体功能测定以及皮肤驻留骨髓细胞群的操作 小鼠模型以及本申请中提出的代谢组学等研究不仅将提升该项目 同时，他的科学和职业进步也将得到强有力的指导的大力支持。 团队成员包括 Tiffany Scharschmidt 博士、Clifford Lowell、Michael Rosenblum 和 Peter Turnbaugh。 此外，通过在当地和国际会议上的演讲以及正式和非正式的培训 加州大学旧金山分校的 Dhariwala 博士将通过强有力的培训，推进他向独立的过渡。 计划和良好的培训环境将使Dhariwala博士能够为自己开拓出一片天地，并建立 一项研究共生微生物对骨髓免疫影响的独立研究项目 新生儿屏障组织的发育。