Optogenetic control of vascular function during pregnancy

妊娠期血管功能的光遗传学控制

基本信息

批准号：
10217625
负责人：
Ramon Lorca
金额：
$ 23.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217625
关键词：
Acute Address Adverse effects Animal Model Animals Area Arteries Blood Pressure Blood Vessels Blood flow Caliber Cardiac Output Cardiovascular Diseases Cell membrane Cells Cervical Child Chimeric Proteins Complication Contralateral Disease Elderly Etiology Fetal Death Fetal Growth Fetal Growth Retardation Fetal Mortality Statistics Fiber Fiber Optics Foundations Goals Heart Rate Hour Human Hypoxia Immunohistochemistry Impairment Implant In Vitro Infant Health Infant Mortality Intervention Late pregnancy Left Life Ligation Light Maternal Health Measures Modeling Monitor Morphology Mothers Mus Myography Neonatal Nutrient Opsin Optics Organ Pathology Physiological Placenta Positioning Attribute Predisposition Pregnancy Preventive therapy Procedures Process Reproducibility Reproductive Health Risk Role SM 22 muscle protein Skin Smooth Muscle Smooth Muscle Myocytes Stress Techniques Technology Testing Therapeutic Time Transgenic Mice Transgenic Organisms Ultrasonography Uterus Vagus nerve structure Vascular Smooth Muscle Vasoconstrictor Agents Weight Whole Blood Wild Type Mouse Work adverse outcome behavioral study cardiovascular disorder risk cranium experimental study fetal genetically modified cells implantation improved in vivo infant morbidity innovation microbial mouse model neonatal death neuronal circuitry novel novel therapeutics optogenetics perinatal period pregnant prevent promoter protein expression pup response selective expression stillbirth subcutaneous therapeutically effective therapy development tool vascular bed vasoconstriction

项目摘要

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.

宫内生长受限（IUGR）会增加死产和新生儿死亡的风险。出生时IUGR的不利影响远远超出围产期，增加晚年患心血管疾病等疾病的风险。血管对妊娠的适应受损是 IUGR 的主要原因。为了了解受损的子宫脉管系统对孕产妇和婴儿健康的影响，我们建议使用光遗传学技术来操纵活体动物的子宫血流。光遗传学是一种创新技术，其中转基因细胞表达光激活的微生物视蛋白（例如视紫红质通道蛋白-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开发一种新颖、可靠且生理相关的 IUGR 小鼠模型。为了实现这一目标，我们建议实施两个综合科学目标。在目标 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。目标 2 将解决光刺激在体内收缩子宫动脉、减少子宫动脉血流量并产生 IUGR 的能力。目前减少子宫血流量的小鼠模型需要结扎子宫动脉，这会产生不良后果，例如胎儿死亡率高和重复性低。我们的光遗传学 IUGR 模型将更好地控制血流操纵程度，增强实验的重复性，提高刺激的选择性，并降低胎儿死亡率。该项目将首次将光遗传学应用于体内子宫血管功能的研究。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。