S1P as regulator of neonatal mucosal immune development and injury

S1P作为新生儿粘膜免疫发育和损伤的调节剂

基本信息

批准号：
10039799
负责人：
Brigida Agnese Rusconi
金额：
$ 13.69万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-17 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10039799
关键词：
Ablation Address Adult Advisory Committees Affect Age Agonist Animal Experiments Animal Model Animals Appointment Atypical lymphocyte Biochemistry Bioinformatics Biology Cell Proliferation Cells Ceramides Chronic Complement Data Dendritic Cells Development Development Plans Diagnosis Emigrant Environment Enzymes Event Exposure to Faculty Feces Fluorescent in Situ Hybridization Functional disorder Germ-Free Grant Gut Mucosa Human Human body ITGAX gene Immune Immunology Individual Infant Inflammatory Injury Institution Integration Host Factors Intestinal Diseases Intestines Knockout Mice Knowledge Lamina Propria Lead Lesion Life Lymphocyte Lymphocyte Function Lymphopenia Manuscripts Mass Spectrum Analysis Mature T-Lymphocyte Mediating Mentored Research Scientist Development Award Mentors Metabolism Microbiology Modeling Molecular Biology Morbidity - disease rate Mucosal Immunity Mucous Membrane Mus Necrotizing Enterocolitis Neonatal Newborn Infant Outcome Pathology Peripheral Pharmacology Phenotype Population Premature Infant Preparation Prevention strategy Process Production Publishing Research Research Personnel Role Shapes Signal Transduction Signaling Molecule Site Small Intestines Specimen Sphingolipids Sphingosine-1-Phosphate Receptor Stimulus T-Lymphocyte Testing Thymus Gland Time Tissues Training Very Low Birth Weight Infant Work Writing bacterial community base career career development cell type cohort cytokine dysbiosis feeding gut bacteria gut microbiota host-microbe interactions human data human microbiota hypoxia neonatorum improved in vivo inflammatory disease of the intestine interest lymph nodes mature animal metabolomics microbial microbial community microbiota migration mortality mouse model mucosal microbiota neonate novel prevent pup receptor residence response secondary lymphoid organ skills sphingosine 1-phosphate thymocyte trafficking

项目摘要

SUMMARY Dr. Rusconi has a long-standing interest in host microbial interactions. Her work has focused on infants born preterm, who are exceptionally prone to life-threatening gut-associated pathology, most notably necrotizing enterocolitis (NEC). The absence of preventive strategies for NEC and its abysmal outcomes, compelled Dr. Rusconi to perform a broad range metabolomics analysis of pre-event NEC specimens to better understand its pathophysiology. A unique sphingolipid profile emerged, which was confirmed in a larger cohort by targeted mass spectrometry. Sphingolipids perform diverse functions in the human body. Sphingosine-1-phosphate (S1P), a sphingolipid metabolite, is an important signaling molecule that promotes lymphocyte migration. The sensing of S1P by S1P receptor 1 (S1P1) is antagonized in vivo by multiple S1P1 agonists, such as SEW2871, through the internalization and degradation of the receptor. By treating neonatal mice with SEW2871 she observed the predicted systemic lymphopenia and and increase in dendritic and T cells in the small intestine lamina propria. The accumulation of these cells in the lamina propria was not observed in adult mice. Aim 1 will focus on identifying age-specific functional responses of the small intestinal lamina propria upon S1P antagonism. Dr. Rusconi will complement pharmacological data with cell-type specific S1P1 KO mice to address cell-specific requirements. The sphingolipid signature and dysbiosis appear in the same pre-NEC interval. Aim 2 focuses on determining their relationship. Germ-free mice will be colonized with dysbiotic or control preterm microbiota to assess impact on sphingolipids. Fecal content from animals used in Aim 1 will be used to determine the impact of S1P antagonism on the microbiota. Finally, in Aim 3, Dr. Rusconi will combine S1P1 antagonism and dysbiotic preterm microbiota with the NEC-like injury model. She will dissect the role of accumulating lymphocyte populations and altered microbiota on exacerbating NEC-like lesions. Completion of this proposal will provide much needed information on the role of S1P signaling in mucosal immunity establishment and its interplay with the microbiota in the maturing intestine, an interval of life during which NEC occurs. Specifically, this K01 award will allow Dr. Rusconi to improve her ability to plan and conduct animal experiments, refine her immunology skills, and provide her with didactic and practical training in grant writing and manuscript preparation, in a highly mentored environment. Dr. Rusconi’s Institution is supporting her effort with a junior faculty appointment, space, and protected time to perform this work. Her advisory committee consists of her primary mentor Dr. Phillip Tarr, co-mentors Drs. Rodney Newberry and Gautam Dantas, who are investigators with complementary expertise in mucosal immunity, microbe-host interactions, animal models of intestinal disease, and human microbiota modeling. Dr. Rusconi’s Career Development Plan adds to her training in biochemistry, molecular biology, microbiology, and bioinformatics. In summary, this K01 grant will provide Dr. Rusconi the skills to launch an independent research career, amalgamating bioinformatics and experimental biology.

概括鲁斯科尼博士长期以来对宿主微生物相互作用感兴趣，她的工作重点是出生的婴儿。早产儿，特别容易出现危及生命的肠道相关病变，尤其是坏死性病变小肠结肠炎 (NEC) 缺乏针对 NEC 的预防策略及其糟糕的结果，迫使 Dr. Rusconi 对事件前 NEC 样本进行广泛的代谢组学分析，以更好地了解其出现了独特的鞘脂谱，并通过靶向研究在更大的队列中得到了证实。鞘脂在人体内发挥多种功能。 (S1P) 是一种鞘脂代谢产物，是促进淋巴细胞迁移的重要信号分子。 S1P 受体 1 (S1P1) 对 S1P 的感知在体内被多种 S1P1 激动剂（例如 SEW2871）拮抗，通过用 SEW2871 治疗新生小鼠，她通过受体的内化和降解。观察到预测的全身淋巴细胞减少以及小肠中树突状细胞和 T 细胞的增加在成年小鼠中未观察到这些细胞在固有层中的积累。关注小肠固有层对 S1P 的年龄识别特异性功能反应 Rusconi 博士将用细胞类型特异性 S1P1 KO 小鼠补充药理学数据来解决这一问题。神经鞘脂特征和菌群失调出现在相同的前 NEC 间隔中。 2 重点是确定无菌小鼠将被定植为菌群失调或对照早产小鼠。将使用微生物群来评估目标 1 中使用的动物粪便含量的影响。最后，在目标 3 中，Rusconi 博士将结合 S1P1 拮抗作用。她将剖析积累的作用。淋巴细胞群和微生物群的改变加剧了 NEC 样病变。完成该提案。将提供关于 S1P 信号在粘膜免疫建立中的作用及其作用的急需信息与成熟肠道中的微生物群相互作用，这是 NEC 发生的生命周期。这个K01奖将使Rusconi博士能够提高她计划和进行动物实验的能力，完善她的免疫学技能，并为她提供资助写作和手稿准备方面的教学和实践培训，在一个高度指导的环境中，鲁斯科尼博士的机构正在通过初级教师支持她的努力。她的咨询委员会由她的主要成员组成。导师 Phillip Tarr 博士，共同导师 Rodney Newberry 博士和 Gautam Dantas 博士，他们是研究人员粘膜免疫、微生物与宿主相互作用、肠道疾病动物模型等方面的互补专业知识， Rusconi 博士的职业发展计划增加了她在生物化学方面的培训，分子生物学、微生物学和生物信息学总之，这笔 K01 资助将为 Rusconi 博士提供开展独立研究职业、融合生物信息学和实验生物学的技能。