Protective role of CXCR7 in neonatal hyperoxia-induced systemic vascular dysfunction in adulthood

CXCR7 在新生儿高氧诱导的成年全身血管功能障碍中的保护作用

• 批准号: 10301871
• 负责人: Merline Benny
• 金额: $ 14.95万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-07 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301871
• 关键词: Adult; Age-Months; Agonist; Air; Aorta; Attenuated; Award; Biology; Biomechanics; Blood Vessels; CASP1 gene; CC chemokine receptor 7; Cardiology; Cardiovascular Physiology; Cardiovascular system; Childhood; Culture Media; Data; Development Plans; Endothelial Cells; Endothelium; Exposure to; Fibrosis; Funding; Generations; Goals; Hares; Hour; Hypertension; Impairment; In Vitro; Incidence; Inflammasome; Inflammation; Injury; Interleukin-1 beta; Intervention; Laboratories; Laboratory Research; Life; Link; Longevity; Mentors; Mentorship; Methodology; Molecular; Morbidity - disease rate; Myocardial Ischemia; Neonatal; Neonatal Hyperoxic Injury; Newborn Infant; Outcome; Oxygen; Pediatrics; Perinatal Care; Pharmacology; Phase; Placebos; Play; Positioning Attribute; Premature Birth; Premature Infant; Prevention; Production; Public Health; Rattus; Research; Rodent; Role; Signal Transduction; Smooth Muscle Myocytes; Stroke; Survivors; Testing; Therapeutic; Time; Training; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Universities; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Work; career; career development; cytokine; experience; genetic approach; improved; in vivo; inhibitor/antagonist; insight; medical schools; meetings; neonatal care; novel; organ injury; pre-clinical; prevent; professor; receptor; repaired; skills; therapeutic development; vascular inflammation; vascular injury

PROJECT SUMMARY/ ABSTRACT With the improvement in perinatal and neonatal care, a new generation of preterm survivors are now reaching adulthood who have increased incidence of cardiovascular morbidities. This a public health concern. Most preterm infants are exposed to supraphysiological oxygen levels. Neonatal hyperoxia exposure in preterm infants increases vascular stiffness in childhood, leading to hypertension, stroke and ischemic heart disease in adult life. However, little is understood about the molecular mechanisms linking neonatal hyperoxia exposure and systemic vascular stiffness. Currently, there are no strategies to prevent the long-term systemic vascular complications seen in preterm infants. This proposal will provide insights into the underlying mechanisms that drive neonatal hyperoxia-induced systemic vascular stiffness and will identify novel targets to reduce vascular diseases in preterm survivors across their lifespan. In this project, Dr. Benny proposes to determine the molecular mechanisms by which endothelial Chemokine Receptor 7 (CXCR7) decreases neonatal hyperoxia-induced systemic vascular stiffness. Aim 1 will test the hypothesis that endothelial CXCR7 decreases neonatal hyperoxia-induced systemic vascular stiffness by suppressing Transforming Growth Factor-β signaling in smooth muscle cells. Aim 2 will test the hypothesis that endothelial CXCR7 attenuates neonatal hyperoxia-induced smooth muscle cell fibrosis by downregulating endothelial inflammasome signaling. Dr. Benny is firmly committed to a career focused on investigating the early origins of vascular morbidities in preterm survivors. Her long-term goal is to translate her experimental laboratory research into the development of therapeutic strategies that could ameliorate the vascular morbidities in the preterm survivors. If these goals are achieved, her work will have a lasting impact on the cardiovascular outcomes of the preterm survivors across their lifespan. She is strongly supported in her career and research goals by her mentors and her division at the University of Miami Miller School of Medicine. She currently holds a position as an Assistant Professor of Pediatrics with 75% protected time for research, start-up funds for her laboratory, independent laboratory and office space. This K08 award will allow Dr. Benny to undertake formal scientific training in vascular injury and stiffness. Under the guidance of her primary mentor, Dr. Omaida Velazquez, her co-mentor Dr. Roberto Vazquez-Padron and her mentoring committee which includes Dr. Joshua Hare, Dr. Karen Young, Dr. Claudia Rodrigues and Dr. Shu Wu, she is fully equipped to advance her skills in both in vivo and in vitro methodologies described for assessing vascular injury and stiffness. In addition, she will achieve her training goals through a career development plan that consists of intensive mentorship, participation in institutional scientific and career development seminars, attendance and presentation at national meetings. Completion of this comprehensive training plan will provide Dr. Benny with the skills and experience necessary to successfully compete for independent funding in the next phase of her career.

项目摘要/摘要 随着围产期和新生儿护理的改善，新一代早产幸存者现在正在 心血管疾病发病率增加的成年人。这是一个公共卫生问题。多数 早产儿暴露在超生理氧气水平下。早产儿新生儿高氧暴露 增加儿童时期的血管僵硬，导致成人高血压、中风和缺血性心脏病 生活。然而，对新生儿高氧暴露与新生儿缺氧的分子机制知之甚少。 全身血管僵硬。目前，还没有预防长期系统性血管病变的策略。 早产儿的并发症。这项提案将提供对以下基本机制的见解 促进新生儿高氧诱导的全身血管僵硬，并将确定减少血管的新靶点 早产幸存者一生中的疾病。 在这个项目中，本尼博士建议确定内皮细胞趋化因子 受体7(CXCR7)降低新生儿高氧诱导的全身血管僵硬。目标1将测试 内皮细胞CXCR7通过降低新生儿高氧诱导的全身血管僵硬的假说 抑制平滑肌细胞中的转化生长因子-β信号。目标2将检验这一假设 内皮细胞CXCR7通过下调血管内皮细胞CXCR7的表达减轻新生高氧诱导的血管平滑肌细胞纤维化 内皮细胞炎症体信号。 本尼博士坚定地致力于研究血管疾病的早期起源。 早产幸存者。她的长期目标是将她的实验实验室研究转化为开发 可以改善早产幸存者血管发病率的治疗策略。如果这些目标 她的工作将对全世界早产幸存者的心血管结局产生持久的影响 他们的寿命。在她的事业和研究目标上，她得到了她的导师和她在 迈阿密大学米勒医学院。她目前担任麻省理工学院的助理教授 儿科有75%的受保护时间用于研究，她的实验室、独立实验室和 办公空间。 这一K08奖项将允许Benny博士在血管损伤和僵硬方面进行正式的科学培训。在……下面 她的主要导师Omaida Velazquez博士、她的共同导师Roberto Vazquez-Padron博士和 她的指导委员会包括约书亚·黑尔博士、凯伦·杨博士、克劳迪娅·罗德里格斯博士和舒博士 吴女士说，她完全有能力提高体内和体外评估方法方面的技能 血管损伤和僵硬。此外，她还将通过职业发展计划实现她的培训目标 这包括密集的指导，参加机构科学和职业发展研讨会， 出席和介绍国家会议。完成这项全面的培训计划将提供 本尼博士拥有成功竞争下一届独立资助所需的技能和经验 这是她职业生涯的一个阶段。