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

项目摘要/摘要

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.