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: 10308095
• 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/10308095
• 关键词: Advisory Committees; Affect; American; Award; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Assay; Blood; Blood Vessels; 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; Maternal Health; Maternal-Fetal Exchange; Mediating; Mentors; Mentorship; Methods; Modeling; 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 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; Virus Diseases; Western Blotting; Work; adaptive immune response; adverse pregnancy outcome; base; career development; cellular targeting; conditional knockout; congenital infection; cost; cytokine; disability; epigenomics; fetal; functional outcomes; health of the mother; healthy pregnancy; in vivo; innovation; instructor; interest; interleukin-15 receptor; macrophage; 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.

项目摘要 这五年的指导临床科学家研究职业发展奖提案的总体目标 是让我成为生殖免疫学领域的一名富有成效的独立学术研究者。 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于 免疫失调对胎儿和母亲妊娠不良后果的公共卫生威胁。我 毕业于美国儿科委员会加速研究路径住院医师， 我在费城儿童医院（CHOP）完成了我的新生儿围产期医学奖学金， 宾夕法尼亚大学（Penn）我加入了CHOP和宾夕法尼亚大学的教师，担任主治医师， 新生儿科讲师。我的导师，爱德华·M。贝伦斯是一名内科医生 科学家，具有长期的科学创新记录，并为学员提供出色的培训 各级作为国际公认的先天免疫和炎症性疾病专家， 贝伦斯的工作补充了我自己的工作，因此我们准备提高生产力。我的科学顾问委员会 包括在拟议工作的所有方面具有集体专业知识的科学家和医学科学家， 胎盘生物学到下一代测序我也非常幸运地得到了 CHOP和Penn的联合资源是无与伦比的。 从科学的角度来说，这个建议的重点是我在博士的指导下发现的新型巨噬细胞的作用。 Behrens，称为CD 122 + Mac，在正常和先兆妊娠。在小鼠和人类的子宫中富集， CD 122 +Macs表达高水平的CD 122，这是对白细胞介素-15（IL-15）反应性的标志。这些 当暴露于IL-15时，新的Macs信号和功能，令人惊讶，因为杀手淋巴细胞像自然杀手 (NK)细胞而不是Macs是IL-15的经典靶点。IL-15的动态平衡被破坏与 妊娠的许多不良后果，包括先兆子痫和胎儿胎盘生长异常， 通过未知的机制。根据先前的文献和我的初步数据，我的中心假设是：IL- 15不仅通过维持NK细胞，而且通过调节NK细胞的表达， 新的CD 122 + Mac的炎症特性。本提案的目的是：1）建立机制， CD 122 +Macs对IL-15的生物化学和转录应答，以及2）IL-15依赖性要求， 妊娠期体内CD 122 +Macs。这一建议将填补有关该机制知识方面的重大空白 IL-15通过其作用于新的细胞靶点以确保妊娠期间的母体和胎儿健康。在 我的职业发展目标是成为生殖免疫学领域的领导者， 科学建议补充了我目前在细胞免疫学方法方面的熟练程度， 先进的生殖生物学和生物信息学方法。