Optogenetic control of vascular function during pregnancy

宫内生长受限（IUGR）增加死产和新生儿死亡的风险。出生时患有先天性先天性疾病的不利影响远远超出了围产期，增加了日后患心血管疾病等疾病的风险。血管对妊娠的适应性受损是IUGR的主要原因。为了了解子宫血管受损对母婴健康的影响，我们建议使用光遗传学技术来操纵活体动物的子宫血流。光遗传学是一项创新技术，其中转基因细胞表达光激活的微生物视蛋白（例如，通道视紫红质- 2，ChR2），然后可以在体内选择性地受到光刺激。我们的目标是利用光遗传学技术建立一种新颖、可靠和生理相关的小鼠IUGR模型。为了实现这一目标，我们建议进行两个综合的科学目标。在Aim 1中，我们将确定体外光刺激对妊娠平滑肌特异性ChR2转基因小鼠子宫动脉功能的影响。目的2将探讨光刺激在体内收缩子宫动脉的能力，减少子宫动脉血流量并产生IUGR。目前减少子宫血流量的小鼠模型需要结扎子宫动脉，这有不良后果，如胎儿死亡率高，可重复性低。我们的光遗传学IUGR模型将更好地控制血流操纵程度，增强实验的可重复性，提高刺激的选择性，并降低胎儿死亡率。本项目将首次将光遗传学应用于子宫血管功能的体内研究。重要的是，我们的建议可以为将光遗传学应用于体内其他血管床的研究提供基础。

Intrauterine growth restriction (IUGR) increases the risk of stillbirth and neonatal death. The adverse effects of being born IUGR extend well beyond the perinatal period, increasing the risk of cardiovascular disease, among others, in later life. Impaired vascular adaptation to pregnancy is a predominant contributor to IUGR. To understand the effects of impaired uterine vasculature on maternal and infant health, we propose using optogenetics technology for manipulating uterine blood flow in live animals. Optogenetics is an innovative technique in which genetically modified cells express light-activated microbial opsins (e.g., channelrhodopsin- 2, ChR2), which can then be selectively stimulated by light in vivo. Our goal is to develop a novel, reliable and physiologically relevant murine model of IUGR using optogenetics. To address this goal, we propose to conduct two integrated scientific aims. In Aim 1, we will determine the effect of in vitro light stimulation on uterine artery function in pregnant smooth muscle specific ChR2 transgenic mice. Aim 2 will address the capacity for light stimulation to constrict the uterine artery in vivo, reducing uterine artery blood flow and producing IUGR. Current murine models for reducing uterine blood flow require uterine artery ligations, which have undesirable consequences such as high rate of fetal death and low reproducibility. Our optogenetic IUGR model will provide better control of the degree of blood flow manipulation, enhanced reproducibility among experiments, improved selectivity of the stimulation, and reduced fetal mortality. This project will be the first to apply optogenetics to the study of uterine vascular function in vivo. Importantly, our proposal can provide the foundation for applying optogenetics to the study of other vascular beds in vivo.