Role of commensal bacteria in regulating neutrophil-mediated host defense in neonates

共生细菌在调节新生儿中性粒细胞介导的宿主防御中的作用

• 批准号: 9272270
• 负责人: Hitesh Deshmukh
• 金额: $ 16.3万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272270
• 关键词: Address; Adoptive Transfer; Advisory Committees; Antibiotics; Antibodies; Basic Science; Birth; Caring; Cause of Death; Cells; Cellular biology; Clinical Skills; Committee Members; Complement; Dendritic Cells; Development; Environment; Escherichia coli; Faculty; Fellowship; Flow Cytometry; Gene Targeting; Goals; Granulopoiesis; Growth; Homeostasis; Host Defense; Host resistance; IL17 gene; Immune; Immune signaling; In Vitro; Innate Immune Response; Institute of Medicine (U.S.); Institutes; Interleukin-1 beta; Interleukin-17; Interleukins; International; Intestines; Lymphoid Cell; Mediating; Mediator of activation protein; Medical; Medical center; Medicine; Mentors; Morbidity - disease rate; Mus; Natural Immunity; Neonatal; Neutropenia; Pediatric Hospitals; Pediatrics; Pharmacology; Philadelphia; Physicians; Postdoctoral Fellow; Premature Infant; Probiotics; Production; Program Development; Regulation; Research; Research Personnel; Residencies; Resistance; Resistance to infection; Resources; Risk; Role; Scientist; Sepsis; Symbiosis; Training; Training Programs; Transgenic Mice; Vulnerable Populations; authority; career; career development; commensal microbes; cytokine; developmental immunology; in vivo; interleukin-23; member; mortality; neonatal death; neonatal sepsis; neonate; neutrophil; novel therapeutic intervention; postnatal; professor; public health relevance; reconstitution; skills

 DESCRIPTION (provided by applicant): This proposal describes a 4-year training program for the development of my academic career in Neonatal Medicine. I have completed formal residency in General Pediatrics and subspecialty fellowship training in Neonatal Medicine at the Children's Hospital of Philadelphia (CHOP). I am now expanding my scientific skills in developmental immunology and neonatal innate immunity and developing my clinical skills in taking care of preterm neonates and infants as an Assistant Professor of Pediatrics at Cincinnati Children's Hospital Medical Center (CCHMC). Dr. Jeffrey Whitsett, an accomplished neonatologist, renowned developmental biologist and a member of the Institute of Medicine (IOM) will mentor my scientific development. Dr. Whitsett is the Vice- Chair for Basic Science Research at CCHMC and has mentored more than 30 physician-scientists. Dr. Harinder Singh, an investigator with the Howard Hughes Medical Institute (HHMI) and an international authority in developmental immunology and dendritic cell biology will complement Dr. Whitsett. Dr. Singh has successfully mentored several junior faculty members and postdoctoral fellows. To further promote my scientific development, I have established a research advisory committee of highly regarded physician scientists consisting of Dr. Sing Sing Way and Dr. Scott Worthen. The proposed research focuses on the role of commensal bacteria in developmental regulation of innate immune responses to sepsis, the leading cause of death in neonates. I found that disruption of commensal bacteria by antibiotics suppressed postnatal neutrophil production and made the neonatal mice more susceptible to Escherichia coli (E. coli), the leading cause of neonatal sepsis. The cytokine, interleukin (IL) 17 is a major homeostatic mechanism for regulation of neutrophil production. I found that antibiotics decreased the number of IL-17 producing innate lymphoid cells (ILC) in the intestine. Reconstitution of commensal bacteria restored the number of IL-17 producing ILC, promoted postnatal neutrophil production and restored the neonate's resistance to E. coli. I now propose to dissect the immune signals by which commensal bacteria regulate neutrophil production and control neonatal resistance to infection. In Aim 1, I will employ a combination of flow cytometry, bacterial reconstitution; transgenic mice to selective ablate immune cells and use adoptive transfer to identify the specific cells that detect commensal bacteria to regulate neonatal host defense. In Aim 2, I will use a combination of ex vivo studies, gene targeted mice and antibody-mediated neutralization to determine how commensal bacteria cells interact with ILC to regulate postnatal neutrophil production and control neonatal host resistance. These studies will clarify the role of commensal bacteria in the developmental regulation of neutrophil number and explain why disruption of normal intestinal commensals results in increased risk of neonatal sepsis. This will lead to better probiotic, antibiotic, and pharmacologic strategies for immune support of the neonates and thus reduce the mortality and morbidity in this vulnerable population. CCHMC provides an ideal scientific environment for my training as a physician-scientist. I will take advantage of the intellectual strength and academic track record of my mentor and scientific advisory committee members, and the robust expertise and resources afforded at CCHMC to accomplish this proposed training program.

 描述（由申请人提供）：该提案描述了一个为期 4 年的培训计划，用于发展我在新生儿医学领域的学术生涯。我已在费城儿童医院 (CHOP) 完成了普通儿科的正式住院医师培训和新生儿医学专科进修培训。作为辛辛那提儿童医院医疗中心 (CCHMC) 的儿科助理教授，我现在正在拓展我在发育免疫学和新生儿先天免疫方面的科学技能，并发展我照顾早产新生儿和婴儿的临床技能。 Jeffrey Whitsett 博士是一位卓有成就的新生儿学家、著名的发育生物学家和医学研究所 (IOM) 成员，他将指导我的科学发展。 Whitsett 博士是 CCHMC 基础科学研究副主席，指导过 30 多名医师科学家。 Harinder Singh 博士是霍华德休斯医学研究所 (HHMI) 的研究员，也是发育免疫学和树突状细胞生物学领域的国际权威，他将补充 Whitsett 博士的工作。辛格博士成功指导了几位初级教员和博士后研究员。为了进一步促进我的科学发展，我成立了一个由备受尊敬的医学科学家组成的研究顾问委员会，其中包括 Sing Sing Way 博士和 Scott Worthen 博士。拟议的研究重点是共生细菌在败血症先天免疫反应发育调节中的作用，败血症是新生儿死亡的主要原因。我发现抗生素破坏共生细菌会抑制出生后中性粒细胞的产生，并使新生小鼠更容易受到大肠杆菌（E. coli）的感染，而大肠杆菌是新生儿败血症的主要原因。细胞因子白细胞介素 (IL) 17 是调节中性粒细胞生成的主要稳态机制。我发现抗生素减少了肠道中产生 IL-17 的先天淋巴细胞 (ILC) 的数量。共生细菌的重建恢复了产生IL-17的ILC的数量，促进了出生后中性粒细胞的产生并恢复了新生儿对大肠杆菌的抵抗力。我现在建议剖析共生细菌调节中性粒细胞产生和控制新生儿对感染的抵抗力的免疫信号。在目标 1 中，我将结合使用流式细胞术和细菌重建；转基因小鼠选择性地消除免疫细胞，并使用过继转移来识别检测共生细菌的特定细胞，以调节新生儿宿主的防御。在目标 2 中，我将结合离体研究、基因靶向小鼠和抗体介导的中和作用来确定共生细菌细胞如何与 ILC 相互作用，从而调节出生后中性粒细胞的产生并控制新生儿宿主抵抗力。 这些研究将阐明共生细菌在中性粒细胞数量发育调节中的作用，并解释为什么正常肠道共生菌的破坏会导致新生儿败血症的风险增加。这将带来更好的益生菌、抗生素和药物策略来支持新生儿的免疫，从而降低这一弱势群体的死亡率和发病率。 CCHMC 为我作为一名医师科学家的培训提供了理想的科学环境。我将利用我的导师和科学咨询委员会成员的智力优势和学术记录，以及 CCHMC 提供的强大的专业知识和资源来完成这项拟议的培训计划。