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: 10653924
• 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/10653924
• 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; Institution; Interleukin-1 beta; Intervention; Laboratories; Laboratory Research; Life; Link; Longevity; Membrane; Mentors; Mentorship; Methodology; Molecular; Morbidity - disease rate; Myocardial Ischemia; Neonatal; Neonatal Hyperoxic Injury; Newborn Infant; Outcome; Oxygen; Pediatrics; Perinatal; 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; Translating; Universities; Vascular Diseases; Vascular Smooth Muscle; Vascular remodeling; Work; career; career development; endothelial repair; experience; genetic approach; improved; in vivo; inhibitor; insight; laboratory experiment; medical schools; meetings; neonatal care; novel; organ injury; pharmacologic; pre-clinical; prevent; professor; profibrotic cytokine; receptor; skills; therapeutic development; translational potential; 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.

项目总结/摘要 随着围产期和新生儿护理的改善，新一代的早产幸存者现在已经达到 心血管疾病发病率增加的成年人。这是一个公共卫生问题。最 早产儿暴露于超生理氧气水平。早产儿新生儿高氧暴露 增加儿童时期的血管硬度，导致成年后的高血压、中风和缺血性心脏病 生活然而，对新生儿高氧暴露与高氧代谢的分子机制知之甚少。 全身血管僵硬。目前，还没有预防长期全身性血管损伤的策略。 早产儿常见的并发症。该提案将提供对潜在机制的见解， 驱动新生儿高氧诱导的全身血管僵硬，并将确定新的靶点，以减少血管紧张素转换酶 早产儿存活者一生中的疾病。 在这个项目中，本尼博士建议确定内皮趋化因子的分子机制， 受体7（CXCR 7）降低新生儿高氧诱导的全身血管僵硬度。目标1将测试 假设内皮细胞CXCR 7通过以下途径降低新生儿高氧诱导的全身血管僵硬度： 抑制平滑肌细胞中的转化生长因子-β信号传导。目标2将检验以下假设： 内皮细胞CXCR 7通过下调新生儿高氧诱导的平滑肌细胞纤维化 内皮炎性体信号传导。 博士本尼坚定地致力于研究血管疾病的早期起源， 早产儿幸存者她的长期目标是将她的实验室研究转化为开发 治疗策略，可以改善血管发病率在早产幸存者。如果这些目标 她的工作将对早产幸存者的心血管结局产生持久的影响， 他们的寿命。她在她的职业生涯和研究目标的大力支持，她的导师和她的部门在 迈阿密大学米勒医学院。她目前担任助理教授， 儿科有75%的保护时间用于研究，启动资金为她的实验室，独立的实验室和 办公空间。 这个K 08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。下 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，其中包括博士约书亚野兔，博士卡伦杨，博士克劳迪娅罗德里格斯和博士舒 吴，她完全有能力提高她在体内和体外方法学方面的技能， 血管损伤和僵硬。此外，她还将通过职业发展计划来实现自己的培训目标 这包括密集的指导，参加机构科学和职业发展研讨会， 出席国家会议并作报告。完成这一全面的培训计划将提供 博士本尼的技能和必要的经验，成功地竞争独立的资金，在未来的 她职业生涯的一个阶段。

项目成果

Maternal SARS-CoV-2, Placental Changes and Brain Injury in 2 Neonates.

• DOI: 10.1542/peds.2022-058271
• 发表时间: 2023-05-01
• 期刊: PEDIATRICS
• 影响因子: 8
• 作者: Benny, Merline;Bandstra, Emmalee S.;Saad, Ali G.;Lopez-Alberola, Roberto;Saigal, Gaurav;Paidas, Michael J.;Jayakumar, Arumugam R.;Duara, Shahnaz
• 通讯作者: Duara, Shahnaz

Educational Review: The Impact of Perinatal Oxidative Stress on the Developing Kidney.

• DOI: 10.3389/fped.2022.853722
• 发表时间: 2022
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6

Comparative Effects of Bone Marrow-derived Versus Umbilical Cord Tissue Mesenchymal Stem Cells in an Experimental Model of Bronchopulmonary Dysplasia.

• DOI: 10.1093/stcltm/szab011
• 发表时间: 2022-03-17
• 期刊: Stem cells translational medicine
• 影响因子: 6
• 作者: Benny M;Courchia B;Shrager S;Sharma M;Chen P;Duara J;Valasaki K;Bellio MA;Damianos A;Huang J;Zambrano R;Schmidt A;Wu S;Velazquez OC;Hare JM;Khan A;Young KC
• 通讯作者: Young KC

Mesenchymal Stem Cell-derived Extracellular Vesicles Prevent Experimental Bronchopulmonary Dysplasia Complicated By Pulmonary Hypertension.

• DOI: 10.1093/stcltm/szac041
• 发表时间: 2022-08-23
• 期刊: STEM CELLS TRANSLATIONAL MEDICINE
• 影响因子: 6
• 作者: Sharma, Mayank;Bellio, Michael A.;Benny, Merline;Kulandavelu, Shathiyah;Chen, Pingping;Janjindamai, Chawisa;Han, Chenxu;Chang, Liming;Sterling, Shanique;Williams, Kevin;Damianos, Andreas;Batlahally, Sunil;Kelly, Kaitlyn;Aguilar-Caballero, Daniela;Zambrano, Ronald;Chen, Shaoyi;Huang, Jian;Wu, Shu;Hare, Joshua M.;Schmidt, Augusto;Khan, Aisha;Young, Karen
• 通讯作者: Young, Karen