Platelet-derived serotonin in neonatal pulmonary hypertension

血小板源性血清素在新生儿肺动脉高压中的作用

• 批准号: 9088082
• 负责人: Cassidy A Delaney
• 金额: $ 16.52万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088082
• 关键词: Adult; Affect; Alpha Granule; Animal Model; Area; Award; Biological Assay; Biological Models; Biology; Blood Platelet Disorders; Blood Platelets; Blood Vessels; Cardiopulmonary; Cattle; Cells; Child; Childhood; Colorado; Complement; Complex; Consensus; Data; Development; Developmental Biology; Disease; Echocardiography; Environment; Fibroblasts; Flow Cytometry; Foundations; Functional disorder; Future; Gene Targeting; Genetic; Goals; Hermanski-Pudlak Syndrome; Human; Hypoxia; In Vitro; Individual; Infant; Inflammation; Inflammation Mediators; Inflammatory; Injury; Investigation; Knockout Mice; Knowledge; Life; Lung; Lung diseases; Measures; Mediating; Mediator of activation protein; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Neonatal; Newborn Infant; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physicians; Physiology; Plague; Plasma; Play; Problem Solving; Proliferating; Pulmonary Hypertension; Pulmonary artery structure; Refractory; Research; Risk; Rodent; Role; Scientist; Serotonin; Sheep; Signal Pathway; Signal Transduction; Source; Staging; System; Techniques; Testing; Thrombosis; Tissues; Training; Tryptophan 5-monooxygenase; Universities; Vascular remodeling; Work; experience; fetal; in vivo; inhibitor/antagonist; innovation; lung development; lung injury; mortality; mouse model; neonatal pulmonary hypertension; new therapeutic target; novel; persistent pulmonary hypertension; public health relevance; receptor; research study; treatment strategy; uptake; vascular inflammation

 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.

 描述（由申请人提供）：本申请旨在获得K 08指导临床科学家发展奖，该奖项旨在研究血小板衍生5-羟色胺（5-HT）在新生儿肺动脉高压（PH）中介导肺血管重塑和炎症的新作用。该候选人是科罗拉多大学的一名神经学家，在过去的七年里一直在研究新生儿PH背景下的5-HT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的发病机制的理解存在重大缺陷，特别是在发育中的肺中，导致治疗策略有限，发病率和死亡率高达26- 43%。的 新生儿PH的病理生理学是复杂的和多因素的，并且涉及包括5-HT在内的几种信号通路的改变。大多数5-HT存在于循环血小板中。血小板和血小板衍生的5-HT已被认为是其他疾病中血管炎症的关键介质。现在有一个共识，即血管炎症是几种动物模型和人类PH发病机制的核心组成部分。她的小组已经确定PA成纤维细胞对PH中的血管重塑和炎症至关重要。该提案将测试血小板衍生的5-HT促进成纤维细胞活化的假设目的1是建立导致PH中血浆5-HT增加的机制。目的2是确定血小板源性5-HT是否与PH中的血管重塑有关。HT促进肺成纤维细胞的增殖和炎症激活。目的3，使用血小板5-HT基因缺失小鼠和5-HT信号传导的药理学抑制来确定血小板来源的5-HT是否有助于体内肺血管重塑、炎症和PH。她使用互补的体内方法和体外系统来询问这些目标。Delaney博士的早期工作集中在5-HT在使用绵羊胎儿PH模型调节胎儿肺血管张力中的作用。这项工作为她提供了生理学，药理学和大型动物模型系统的坚实基础。此后，她认识到迫切需要探索5-HT促进PH中肺血管重塑的机制，因为血管重塑是医学难治性PH的主要特征，病理生物学知之甚少，导致死亡率高。虽然胎羊模型提供了几个优点，Delaney博士做出了积极的决定，将她的研究转移到PH小鼠模型，以（1）阐明PH中5-HT增加的来源，（2）使用基因靶向小鼠探索5-HT如何在机制上起作用。HT导致PH患者的血管重塑和炎症。她建立了一个由PH和血小板领域的顶尖科学家组成的导师团队生物学和当地顾问在补充调查领域，以支持她，并确保她的道路走向独立在此期间的奖励。该K 08奖项将允许Delaney博士进行四年的受保护研究，并通过允许她（1）获得执行和解释血小板测定，流式细胞术，分子技术和啮齿动物超声心动图的专业知识和（2）发展发育调节的5-HT信号传导和血小板介导的炎症的专业知识来帮助她的科学发展。在实验技术，发育生物学和细胞信号传导的额外培训是必不可少的，并将准备她提交R 01她的K 08奖励期结束。德莱尼博士的长期学术和研究目标是发展成为一个有成就的和独立的医生，科学家与5-羟色胺介导的PH谁可以识别和回答发育生物学的基本知识差距，有助于在新生儿不利的心肺条件的专业知识。她已经证明了她对这一长期目标的承诺，并在一个优秀的学术环境，以实现这一目标。她有经验，强大的研究背景，导师，机构的支持，并专注于卓越。她很幸运，已经确定了致力于导师与补充，但从她的研究重点不同的专业领域，从而确保她的科学独立性的发展。最终作为一名医生科学家，德莱尼博士致力于解决肺部发育和损伤问题，这些问题继续困扰着早产儿和足月儿。