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：
10219246
负责人：
Brigida Agnese Rusconi
金额：
$ 13.54万
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/10219246
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 lymphocyte trafficking mature animal metabolomics microbial microbial community microbiota migration mortality mouse model mucosal microbiota neonatal mice neonate novel prevent pup receptor residence response secondary lymphoid organ skills sphingosine 1-phosphate thymocyte

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 Rusconi博士对宿主微生物相互作用具有长期的兴趣。她的工作专注于出生的婴儿早产，他们非常容易威胁生命的肠道相关病理，最著名的是坏死小肠结肠炎（NEC）。缺乏NEC及其糟糕结果的预防策略，迫使博士 Rusconi对事件前NEC标本进行广泛的代谢组学分析，以更好地了解其病理生理学。出现了一个独特的鞘脂曲线，该轮廓已在较大的队列中被靶向确认质谱法。鞘脂在人体中发挥了潜水功能。鞘氨醇1-磷酸盐（S1P）是一种鞘脂代谢物，是促进淋巴细胞迁移的重要信号分子。通过多个S1P1激动剂（例如SEW2871）在体内拮抗S1P受体1（S1P1）对S1P的传感通过接收器的内在化和降解。通过用SEW2871治疗新生小鼠观察到了预测的全身淋巴细胞减少症，并增加了小肠中的树突状和T细胞的增加薄片propria。这些细胞在成年小鼠中未观察到这些细胞在椎板中的积累。目标1意志专注于识别小肠道层次的特定年龄特异性功能反应在S1P上对抗。 Rusconi博士将用细胞类型的特定S1P1 KO小鼠补充药物数据来解决细胞特异性要求。鞘脂的特征和营养不良以相同的NEC间隔出现。目的 2专注于确定他们的关系。无菌小鼠将用失调或对照早产殖民微生物群评估对鞘脂的影响。 AIM 1中使用的动物的粪便含量将用于确定 S1P拮抗对微生物群的影响。最后，在AIM 3中，Rusconi博士将结合S1P1拮抗作用具有NEC样损伤模型的不良生物早产。她将剖析积累的作用淋巴细胞群体和恶化NEC样病变的微生物群改变。完成此提案将提供有关S1P信号在粘膜免疫建立及其的作用的急需信息在成熟的肠道中与微生物群的相互作用，这是NEC发生的生活间隔。具体来说，这项K01奖将使Rusconi博士能够提高她计划和进行动物实验的能力，改进她免疫学技能，并在赠款写作和手稿准备方面为她提供教学和实践培训，在备受推崇的环境中。 Rusconi博士的机构正在支持她与初级教师的努力约会，空间和保护这项工作的时间。她的咨询委员会由她的主要导师菲利普·塔尔（Phillip Tarr）博士，联合委托人博士。罗德尼·纽伯里（Rodney Newberry）和高塔·丹塔斯（Gautam Dantas）粘膜免疫，微生物宿主相互作用，肠道疾病动物模型的互补专业知识，和人类微生物群建模。 Rusconi博士的职业发展计划增加了她的生物化学培训，分子生物学，微生物学和生物信息学。总而言之，这项K01赠款将为Rusconi博士提供启动独立研究职业，合并生物信息学和实验生物学的技能。