Physiologic and Genetic Contributions of Impaired Fetal Brain Development in Congenital Heart Disease

项目总结 先天性心脏病(CHD)是最常见的出生缺陷，随着患者存活率的提高 在中-重度冠心病中，成年人的数量现在超过了儿童。死亡率的下降已经发生了变化 研究的重点是改善长期结果和生活质量。最常见的不良后果是 神经发育障碍，发生在50%的中-重度CHD患者中。而在出生后 经过测量的内科和外科因素对这些婴儿的护理和预后起着至关重要的作用。 磁共振成像(MRI)研究已经确定大脑发育受损，甚至在心脏疾病之前 并强调胎儿期是这些畸形演变的时期。这些数据 提示胎儿干预可能是提高高神经发育率的一个重要方面 冠心病的损害。国家心肺血液研究所强调了将研究重点放在 关于减少冠心病神经发育缺陷的预防和治疗策略。这位导师 以病人为导向的职业发展奖很好地契合了这一需求，其目标是描述轨迹 中重度CHD胎儿皮质脑发育障碍的发生及其机制 生理变异和遗传变异之间的相互作用导致了这一人群的大脑破坏。这些 数据将有助于确定可能受益于胎儿神经保护的CHD胎儿的时间和群体 并将为患者咨询的风险预测提供信息。 该奖项将为候选人提供成功开展以下工作所需的教育、培训和指导 这项建议和培养成为一名专注于改善的独立临床医生科学家所需的技能 冠心病患者的神经发育结局。奥蒂诺博士已经在磁共振分析方面积累了专业知识 技巧。因此，该奖项的培训和指导将集中在：1)加强对胎儿的知识 心脏生理学及其在心脏生理学与脑生理学研究中的应用 血流动力学和胎脑发育；以及2)获得遗传和基因组方面的知识和经验 研究以了解遗传变异对大脑皮层发育的贡献。独一无二的 华盛顿大学医学院的环境提供了在这些关键领域进行培训的机会 使用候选人职业发展计划中概述的基础设施、资源和指导。这些 研究活动将提供开发假设驱动的R01所需的初步数据 该奖项第二年的应用，旨在了解生理学和生理学之间的机制相互作用 可能导致中重度CHD脑发育障碍的遗传途径。

PROJECT SUMMARY Congenital heart disease (CHD) is the most common birth defect and, as survival has improved for patients with moderate-severe CHD, adults now outnumber children with this diagnosis. This reduction in mortality has shifted research focus to improving long-term outcomes and quality of life. The most common adverse outcome is neurodevelopmental impairment and occurs in 50% of patients with moderate-severe CHD. While postnatally measured medical and surgical factors play a crucial role in the care and outcomes of these infants, brain magnetic resonance imaging (MRI) studies have identified impaired brain development even before cardiac surgery and have emphasized the fetal period as a time when these abnormalities are evolving. These data suggest fetal interventions may be an important aspect of improving the high rates of neurodevelopmental impairments in CHD. The National Heart, Lung, and Blood Institute has highlighted a need for research focused on preventive and therapeutic strategies for reducing neurodevelopmental deficits in CHD. This Mentored Patient-Oriented Career Development Award aligns well with this need by aiming to characterize the trajectory of disrupted cortical brain development in fetuses with moderate-severe CHD and to understand mechanistic interactions between physiologic and genetic variation that underlie brain disruption in this population. These data will assist in identifying the timing and population of CHD fetuses that may benefit from fetal neuroprotective interventions and will inform risk prediction for patient counseling. This Award will provide the candidate the education, training, and mentoring necessary to successfully undertake this proposal and to develop the skills required to become an independent clinician scientist focused on improving neurodevelopmental outcomes in patients with CHD. Dr. Ortinau has already developed expertise in MR analysis techniques. Thus, the training and mentorship for this award will focus on: 1) enhancing knowledge of fetal cardiac physiology and developing expertise in the association of cardiac physiology with cerebral hemodynamics and fetal brain development; and 2) gaining knowledge and experience in genetic and genomic research to understand the contribution of genetic variation to cerebral cortical development. The unique environment at Washington University School of Medicine provides the opportunity to train in these key areas using the infrastructure, resources, and mentorship outlined in the candidate’s Career Development Plan. These research activities will provide the preliminary data necessary for development of an hypothesis-driven R01 application in Year 2 of this Award, aimed at understanding mechanistic interactions between physiologic and genetic pathways that may underlie disruption of brain development in moderate-severe CHD.