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.

项目摘要/摘要 随着围产期和新生儿护理的改善，新一代的早产生存正在达到 心血管病发病率增加的成年。这是一个公共卫生问题。最多 早产婴儿暴露于超生理氧气水平。早产儿的新生儿高氧 增加童年血管僵硬，导致成人高血压，中风和缺血性心脏病 生活。但是，关于新生儿高氧和接触的分子机制几乎没有理解 全身血管刚度。目前，没有防止长期全身血管的策略 在早产儿中看到的并发症。该提案将提供有关对基本机制的见解 驱动新生儿高氧引起的全身血管刚度，并将确定新的靶标以减少血管 在其寿命中早产中的疾病。 在这个项目中，Benny博士提出了确定内皮趋化因子的分子机制 受体7（CXCR7）降低了新生儿多氧诱导的全身血管僵硬。 AIM 1将测试 内皮CXCR7的假设可降低新生儿多氧诱导的全身血管僵硬。 抑制平滑肌细胞中转化生长因子-β信号传导。 AIM 2将检验以下假设 内皮CXCR7通过下调来减轻新生儿多氧诱导的平滑肌细胞纤维化 内皮炎症体信号传导。 Benny博士首先致力于研究研究血管病变的早期起源的职业 早产。她的长期目标是将她的实验实验室研究转化为发展 可以改善早产生存中血管病变的理论策略。如果这些目标 实现了，她的工作将对遍布早产者的心血管成果产生持久的影响 他们的寿命。她的职业生涯和研究目标得到了强烈的支持，她的导师和她的部门在 迈阿密米勒大学医学院。她目前担任 有75％的研究时间为研究时间，她的实验室，独立实验室和 办公空间。 该K08奖将使Benny博士可以接受血管损伤和僵硬的正式科学培训。在下面 她的主要导师Omaida Velazquez博士的指导 她的心理委员会包括Joshua Hare博士，Karen Young博士，Claudia Rodrigues博士和Shu博士 吴，她完全有能力提高体内和体外方法的技能 血管损伤和僵硬。此外，她将通过职业发展计划实现自己的培训目标 这包括密集的心态，参与机构科学和职业发展中心， 参加国家会议的出席和演讲。该全面培训计划的完成将提供 本尼博士拥有成功竞争独立资金所必需的技能和经验 她职业的阶段。

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