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: 10460572
• 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/10460572
• 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： 早期生命中共生微生物与发育中的免疫系统之间的相互作用形成了 对人类健康和慢性炎症性疾病易感性的影响。东道主实验室之前的研究 其他研究小组已经证明，我们的微生物共生体可以调节驻留在皮肤上的T细胞功能， 尤其是在新生儿窗口期。然而，相对较少的人知道共生关系如何影响 生命早期的皮肤髓系免疫。Dhariwala博士发现，共生微生物影响着 新生儿皮肤髓系间室的组成和功能。具体地说，共生微生物推动 新生儿皮肤中Ly6ChiMHC-IIlo炎性单核细胞的聚集这些细胞有 传统上被研究为炎症的主要介质，以应对感染或其填充能力 空置的组织髓系壁龛。然而，Dhariwala博士的初步研究表明，以前从未探索过的 调节免疫印迹对新生儿皮肤单核细胞的作用。来剖析分子机制， 为了支持这一现象，我们将结合使用转基因小鼠模型、高通量分析 例如，质量细胞术和单细胞RNA测序以及新的体外翻译工具。研究 本申请中提出的将(目标1)剖析共生微生物影响的机制(S) 新生儿皮肤单核细胞募集和功能，(目的2)阐明新生儿皮肤中单核细胞募集和功能的机制(S) 单核细胞有助于皮肤免疫平衡和(目标3)从功能上阐明新生儿的作用 人类皮肤中的单核细胞。这种跨学科方法的结果将有助于我们对早期 发展免疫系统，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达里瓦拉博士在微生物学领域的优势之上， 免疫学和转化学。利用他在东道主实验室建立的工具，如MASS 细胞术，人体皮肤的体外功能分析和皮肤驻留的髓细胞群的操作 小鼠模型，以及这一应用中提出的代谢组学等研究不仅将提升该项目 而且还能推进他的训练。他在科学和事业上的进步将得到强有力的指导 团队包括蒂凡尼·沙尔施密特博士、克利福德·洛厄尔博士、迈克尔·罗森布鲁姆博士和彼得·特恩博博士。 此外，通过在当地和国际会议上的发言以及正式和非正式培训 在加州大学旧金山分校，达里瓦拉博士将推进他向独立的过渡。前景看好的初步数据，强有力的训练 计划和良好的培训环境将使Dhariwala博士能够为自己开辟一个利基市场，并建立 研究共生微生物对髓系免疫影响的独立研究计划 新生儿屏障组织的发育。

项目成果

Commensal myeloid crosstalk in neonatal skin regulates long-term cutaneous type 17 inflammation.

新生儿皮肤中的共生髓系串扰可调节长期皮肤 17 型炎症。

• DOI: 10.1101/2023.09.29.560039
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Dhariwala,MiqdadO;DeRogatis,AndreaM;Okoro,JoyN;Weckel,Antonin;Tran,VictoriaM;Habrylo,Irek;Ojewumi,OluwasunmisolaT;Tammen,AllisonE;Leech,JohnM;Merana,GeilR;Carale,RicardoO;Barrere-Cain,Rio;Hiam-Galvez,KamirJ;Spitzer,Mat
• 通讯作者: Spitzer,Mat

Baby's skin bacteria: first impressions are long-lasting.

• DOI: 10.1016/j.it.2021.10.005
• 发表时间: 2021-12
• 期刊: TRENDS IN IMMUNOLOGY
• 影响因子: 16.8
• 作者: Dhariwala, Miqdad O.;Scharschmidt, Tiffany C.
• 通讯作者: Scharschmidt, Tiffany C.