Functions for novel IL-15-responsive macrophages in the uterus during pregnancy

妊娠期间子宫内新型 IL-15 反应性巨噬细胞的功能

• 批准号: 10524025
• 负责人: Scott Michael Gordon
• 金额: $ 18.53万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524025
• 关键词: Acceleration; Advisory Committees; Affect; American; Award; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Assay; Blood; Cells; Cellular Immunology; Cessation of life; Child Support; Chromatin; Clinical; Complement; Cytokine Signaling; Data; Development; Disease; Distal; Doctor of Philosophy; Embryo; Ensure; Environment; Enzyme-Linked Immunosorbent Assay; Exposure to; Faculty; Fellowship; Fetal Development; Fetal Growth Retardation; Fetal health; Fetus; Flow Cytometry; Foundations; Functional disorder; Funding; Genes; Genetic Transcription; Goals; Growth; Homeostasis; Human; IL2RB gene; Immune; Immunity; Immunologics; Immunologist; Inflammation; Inflammatory; Interferons; Interleukin-10; Interleukin-15; International; Investigation; K-Series Research Career Programs; Kinetics; Knockout Mice; Knowledge; Life; Literature; Lymphocyte; Macrophage; Maternal Health; Maternal-Fetal Exchange; Mediating; Mentors; Mentorship; Methods; Molecular; Mothers; Mus; Myeloid Cells; Natural Immunity; Natural Killer Cells; Neonatal; Neonatology; Nutrient; Outcome; Oxygen; Pathway interactions; Pediatric Hospitals; Pediatrics; Pennsylvania; Personal Satisfaction; Philadelphia; Phosphorylation; Physicians; Placenta; Placental Biology; Play; Population; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Productivity; Property; Public Health; Reproductive Biology; Reproductive Immunology; Research; Research Personnel; Residencies; Resources; Role; STAT3 gene; Scientist; Shapes; Signal Transduction; Stat5 protein; Techniques; Testing; Training; Transposase; Universities; Uterus; Vascular remodeling; Viral; Virus Diseases; Western Blotting; Work; adaptive immune response; adverse pregnancy outcome; career development; cellular targeting; conditional knockout; congenital infection; cost; cytokine; disability; epigenomics; fetal; functional outcomes; health of the mother; healthy pregnancy; in vivo; in vivo Model; inflammatory modulation; innovation; instructor; interest; interleukin-15 receptor; maternal outcome; mouse model; next generation sequencing; novel; perinatal medicine; reproductive; response; transcriptome sequencing; transcriptomics

PROJECT SUMMARY The overall goal of this five-year proposal for a Mentored Clinical Scientist Research Career Development Award is for me to develop into a productive, independent academic investigator in the field of reproductive immunology. I completed an MD and a PhD in the field of basic cellular immunology, and I now seek to apply my interest in dysregulated immunity to the public health threat of adverse fetal and maternal outcomes of pregnancy. I graduated from the American Board of Pediatrics Accelerated Research Pathway for Residency in General, and I completed my Fellowship in Neonatal-Perinatal Medicine at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). I joined the faculty of CHOP and Penn as an Attending Physician and Instructor in the Division of Neonatology. My mentor for this award, Dr. Edward M. Behrens, is a physician- scientist with a longstanding track record of scientific innovation and providing exceptional training to mentees at all levels. As an internationally-recognized expert in innate immunity and inflammatory disorders, Dr. Behrens’s work complements my own, and we are thus poised for productivity. My scientific advisory committee includes scientists and physician-scientists with collective expertise in all aspects of the proposed work, from placental biology to next-generation sequencing. I am also extremely fortunate to have the unreserved support of CHOP and Penn, whose combined resources are unmatched. Scientifically, this proposal focuses on roles for novel macrophages that I discovered under the guidance of Dr. Behrens, called CD122+Macs, in normal and threatened pregnancy. Enriched in the uterus in mice and humans, CD122+Macs express high levels of CD122, the hallmark of responsiveness to interleukin-15 (IL-15). These novel Macs signal and function when exposed to IL-15, surprising because killer lymphocytes like natural killer (NK) cells, not Macs, are the classical targets of IL-15. Disrupted homeostasis of IL-15 is associated with numerous adverse outcomes of pregnancy, including preeclampsia and abnormal feto-placental growth but through unknown mechanisms. Based on prior literature and my preliminary data, my central hypothesis is: IL- 15 exerts its influence over outcomes of pregnancy not only by maintaining NK cells but also by modulating the inflammatory properties of novel CD122+Macs. The aims of this proposal will establish: 1) Mechanisms by which CD122+Macs respond biochemically and transcriptionally to IL-15 and 2) IL-15-dependent requirements for CD122+Macs in pregnancy in vivo. This proposal will close major gaps in knowledge regarding the mechanism by which IL-15 acts on a novel cellular target to ensure maternal and fetal health during pregnancy. In accordance with my career development objective to become a field leader in reproductive immunology, my scientific proposal complements my current proficiency in cellular immunologic methods with training in advanced reproductive biology and bioinformatic methods.

项目概要 指导临床科学家研究职业发展奖五年提案的总体目标 对我来说，是要发展成为生殖免疫学领域一位富有成效的、独立的学术研究者。 我完成了基础细胞免疫学领域的医学博士和博士学位，现在我寻求将我的兴趣应用到 对妊娠不良胎儿和母体结局的公共健康威胁的免疫力失调。 毕业于美国儿科委员会住院医师加速研究途径，并且 我在费城儿童医院 (CHOP) 完成了新生儿围产期医学专科培训，并且 我作为主治医师加入了宾夕法尼亚大学 (Penn) 和 CHOP。 我获得此奖项的导师爱德华·贝伦斯 (Edward M. Behrens) 博士是一位内科医生—— 拥有长期科学创新记录并为学员提供卓越培训的科学家 作为国际公认的先天免疫和炎症性疾病专家，Dr. 贝伦斯的工作与我的工作相辅相成，因此我们为我的科学顾问委员会做好了生产力的准备。 包括在拟议工作的各个方面具有集体专业知识的科学家和医师科学家，从 从胎盘生物学到下一代测序，我也非常幸运能够得到毫无保留的支持。 CHOP 和 Penn 的结合，其资源无与伦比。 从科学角度来说，该提案的重点是我在 Dr. 的指导下发现的新型巨噬细胞的作用。 Behrens，称为 CD122+Macs，在正常妊娠和先兆妊娠中富含于小鼠和人类的子宫中， CD122+Mac 表达高水平的 CD122，这是对白介素 15 (IL-15) 反应性的标志。 当暴露于 IL-15 时，新的 Mac 信号和功能令人惊讶，因为杀伤淋巴细胞像自然杀伤细胞一样 (NK) 细胞（而非 Mac）是 IL-15 的经典靶标 IL-15 的稳态破坏与此相关。 许多妊娠不良后果，包括先兆子痫和胎儿胎盘生长异常，但 根据之前的文献和我的初步数据，我的中心假设是：IL- 15 对妊娠结局的影响不仅通过维持 NK 细胞，还通过调节 新型 CD122+Mac 的炎症特性 该提案的目标是： 1) 机制。 CD122+Macs 对 IL-15 产生生化和转录反应，并且 2) IL-15 依赖性需求 CD122+Macs 在妊娠体内的作用该提案将弥补有关该机制的主要知识空白。 IL-15 通过作用于一个新的细胞靶点来确保妊娠期间母体和胎儿的健康。 根据我的职业发展目标是成为生殖免疫学领域的领导者，我的 科学建议通过以下方面的培训补充了我目前对细胞免疫方法的熟练程度 先进的生殖生物学和生物信息方法。