Platelet-derived serotonin in neonatal pulmonary hypertension

 描述(申请人提供)：这份申请是为了获得K08临床科学家指导发展奖，研究血小板衍生的5-羟色胺(5-HT)在调节新生儿肺动脉高压(PH)的肺血管重塑和炎症中的新作用。候选人是科罗拉多大学的一名新生儿专家，在过去的七年里，他一直在新生儿PH的背景下研究5-羟色胺生物学。肺动脉高压(PH)是一种危及生命的疾病，影响婴儿、儿童和成人。我们对PH的发病机制，特别是对发育中的肺的认识存在重大缺陷，导致治疗策略有限，发病率和死亡率高达26-43%。这个 新生儿PH的病理生理是复杂的、多因素的，涉及包括5-羟色胺在内的多个信号通路的改变。5-羟色胺主要存在于循环中的血小板中。在其他疾病中，血小板和血小板衍生的5-羟色胺已被认为是血管炎症的关键介质。目前已达成共识，认为血管炎症是几种动物模型和人类肺高压发病机制的中心组成部分。她的团队已经证实，PA成纤维细胞在PH的血管重塑和炎症中起着关键作用。这一建议将检验这样一种假设，即血小板衍生的5-羟色胺促进肺高压患者成纤维细胞的激活(增殖和炎性介质的合成)和血管重构。目的一是探讨高血压病患者血浆5-羟色胺升高的机制。目的2确定血小板衍生的5-羟色胺是否促进肺成纤维细胞的增殖和炎症激活。目的3，利用血小板5-羟色胺基因缺失和药物抑制5-羟色胺信号通路的方法，在体内确定血小板衍生的5-羟色胺是否与肺血管重塑、炎症和肺高压有关。她使用补充的体内方法和体外系统来询问这些目标。德莱尼博士的早期工作集中在5-羟色胺在利用绵羊肺高压胎儿模型调节胎儿肺血管张力中的作用。这项工作为她在生理学、药理学和大型动物模型系统方面奠定了坚实的基础。自那以后，她认识到迫切需要探索5-羟色胺在肺血管重构中促进肺血管重构的机制，因为血管重构是医学上难治性肺高压的主要特征，而对病理生物学的了解很少，导致高死亡率。虽然胎羊模型有几个优点，但Delaney博士做出了积极的决定，将她的研究转移到PH的小鼠模型上，以便(1)阐明PH中5-HT增加的来源，(2)使用基因靶标小鼠从机制上探索5-HT如何导致PH中的血管重塑和炎症。她已经建立了一个由PH和血小板生物学领域的一流科学家组成的导师团队，以及互补研究领域的当地顾问，以支持她并确保她在此次获奖期间走上独立的道路。这项K08奖将允许Delaney博士进行四年的保护性研究，并通过使她能够(1)获得执行和解释血小板分析、流式细胞仪、分子技术和啮齿动物超声心动图方面的专业知识，以及(2)开发发育调节的5-羟色胺信号和血小板介导的炎症方面的专业知识，来帮助她的科学发展。这种额外的实验技术、发育生物学和细胞信号方面的培训是必不可少的，并将为她在K08获奖期结束前提交R01做好准备。Delaney博士的长期学术和研究目标是发展成为一名成就卓著的独立内科科学家，在5-羟色胺介导的PH方面具有专长，能够识别和回答导致新生儿心肺疾病的发育生物学的基本知识空白。她已经证明了她对这一长期目标的承诺，并处于一个出色的学术环境中来实现这一目标。她有经验，有很强的研究背景，有导师，有制度支持，有专注于出类拔萃。幸运的是，她找到了忠心耿耿的导师，这些导师具有与她的研究重点相辅相成但又不同的专业知识领域，从而确保了她的科学独立性的发展。最终，作为一名内科科学家，德莱尼博士致力于解决继续困扰早产儿和足月儿的肺部发育和损伤问题。

 DESCRIPTION (provided by applicant): This application is for a K08 Mentored Clinical-Scientist Development Award investigating the novel role of platelet-derived serotonin (5-HT) in mediating pulmonary vascular remodeling and inflammation in neonatal pulmonary hypertension (PH). The candidate is a neonatologist at the University of Colorado who has been studying 5-HT biology in the context of neonatal PH for the past seven years. Pulmonary hypertension (PH) is a life-threatening condition that affects infants, children and adults. There are major deficiencies in our understanding of the pathogenesis of PH, particularly in the developing lung, leading to limited treatment strategies, significant morbidities and mortality rates of 26-43%. The pathophysiology of neonatal PH is complex and multifactorial, and involves alterations in several signaling pathways, including 5-HT. The majority of 5-HT is found within circulating platelets. Platelets and platelet-derived 5-HT have been recognized as key mediators of vascular inflammation in other disease settings. There is now consensus that vascular inflammation is a central component to the pathogenesis of PH in several animal models and humans with PH. Her group has established that PA fibroblasts are critical for vascular remodeling and inflammation in PH. This proposal will test the hypothesis that platelet-derived 5-HT promotes fibroblast activation (proliferation and synthesis of inflammatory mediators) and vascular remodeling in PH. Aim 1 is to establish the mechanism leading to increased plasma 5-HT in PH. Aim 2 is to determine if platelet-derived 5-HT promotes proliferation and inflammatory activation of pulmonary fibroblasts. Aim 3, uses mice genetically depleted of platelet 5-HT and pharmacologic inhibition of 5-HT signaling to determine if platelet-derived 5-HT contributes to pulmonary vascular remodeling, inflammation, and PH in vivo. She uses complementary in vivo methods and in vitro systems to interrogate these aims. Dr. Delaney's early work focused on the role of 5-HT in modulating fetal pulmonary vascular tone using an ovine fetal model of PH. This work provided her with a strong foundation in physiology, pharmacology, and large animal model systems. She has since recognized a critical need to explore the mechanisms by which 5-HT contributes to pulmonary vascular remodeling in PH as vascular remodeling is a principal feature of medically refractory PH, with poorly understood pathobiology leading to high mortality. While the fetal sheep model offers several advantages, Dr. Delaney made the active decision to transition her research to a mouse model of PH in order to (1) elucidate the source of increased 5-HT in PH and (2) use gene targeted mice to explore mechanistically how 5-HT leads to vascular remodeling and inflammation in PH. She has established a mentorship team of premier scientists in the fields of PH and platelet biology, and local advisors in complementary areas of investigation to support her and assure her path towards independence during this award period. This K08 award will allow Dr. Delaney four years of protected research, and aid her scientific development by allowing her to (1) gain expertise in performing and interpreting platelet assays, flow cytometry, molecular techniques, and rodent echocardiography and (2) develop expertise in developmentally regulated 5-HT signaling and platelet mediated inflammation. This additional training in experimental techniques, developmental biology and cell signaling is essential and will prepare her to submit a R01 by the end of her K08 award period. Dr. Delaney's long term academic and research goal is to develop into an accomplished and independent physician-scientist with an expertise in 5-HT mediated PH who can identify and answer fundamental knowledge gaps in developmental biology that contribute to adverse cardiopulmonary conditions in newborn infants. She has demonstrated her commitment to this long-term goal and is in an outstanding academic environment to attain this goal. She has the experience, strong research background, mentorship, institutional support, and focus to excel. She is fortunate to have identified committed mentors with individual areas of expertise that complement but are different from her research focus; thus assuring the development of her scientific independence. Ultimately as a physician-scientist, Dr. Delaney is committed to solving problems in lung development and injury that continue to plague preterm and term infants.