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

项目总结 这项为期五年的临床科学家导师研究职业发展奖提案的总体目标是 对我来说，是要发展成为生殖免疫学领域的一名富有成效的独立学术研究员。 我在基础细胞免疫学领域获得了医学博士学位和博士学位，现在我寻求将我的兴趣应用于 对妊娠不良胎儿和产妇结局的公共健康威胁的免疫失调。我 毕业于美国儿科委员会普通住院医师加速研究路径，以及 我在费城儿童医院(CHOP)完成了新生儿-围产期医学研究，并 宾夕法尼亚大学(宾夕法尼亚)。我加入了乔普和宾夕法尼亚大学，成为一名主治医师 新生儿科讲师。我的这个奖项的导师爱德华·M·贝伦斯博士是一名内科医生- 长期从事科学创新并为学员提供特殊培训的科学家 在所有层面上。作为国际公认的先天免疫和炎症性疾病方面的专家， 贝伦斯的工作与我的工作相辅相成，因此我们已经准备好提高生产率。我的科学顾问委员会 包括在拟议工作的所有方面拥有集体专业知识的科学家和内科科学家，来自 胎盘生物学到下一代测序。我也非常幸运地得到了毫无保留的支持 乔普和宾夕法尼亚大学，他们的资源加起来是无与伦比的。 从科学上讲，这项建议的重点是我在Dr. Behrens，称为CD122+MACs，在正常和先兆妊娠中。在小鼠和人类的子宫中丰富， CD122+Mac表达高水平的CD122，这是对白细胞介素15(IL-15)有反应性的标志。这些 当暴露在IL-15下时，新的Mac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Mac，是IL-15的经典靶点。IL-15的动态平衡紊乱与 妊娠的许多不良后果，包括先兆子痫和胎儿-胎盘发育异常，但 通过未知的机制。根据以前的文献和我的初步数据，我的中心假设是：IL-1 15不仅通过维持NK细胞对妊娠结局产生影响，还通过调节 新型CD122+Mac的炎症特性。这项提案的目标将建立：1)通过以下机制 CD122+Mac在生化和转录方面对IL-15和2)IL-15依赖的需求做出反应 CD122+MACs在体内妊娠。这项提议将弥合关于该机制的主要知识空白。 通过IL-15作用于一种新的细胞靶点，以确保怀孕期间的母婴健康。在……里面 根据我的职业发展目标，成为生殖免疫学领域的领先者，我的 科学提案通过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学方法。

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.