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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：
10380024
负责人：
Ramon Lorca
金额：
$ 19.44万
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 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380024
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 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 ultrasound 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）增加了死胎和新生儿死亡的风险。胎儿宫内发育迟缓的不利影响远远超出围产期，增加了晚年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。为了了解受损的子宫脉管系统对母婴健康的影响，我们建议使用光遗传学技术来操纵活体动物的子宫血流。光遗传学是一种创新技术，其中遗传修饰的细胞表达光激活的微生物视蛋白（例如，channelrhodopsin- 2，ChR 2），然后可以在体内选择性地被光刺激。我们的目标是利用光遗传学开发一种新的、可靠的和生理相关的IUGR小鼠模型。为了实现这一目标，我们建议进行两个综合的科学目标。在目的1中，我们将确定体外光刺激对妊娠平滑肌特异性ChR 2转基因小鼠子宫动脉功能的影响。目的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和产生IUGR的能力。目前用于减少子宫血流的鼠模型需要子宫动脉结扎，这具有不期望的后果，例如高的胎儿死亡率和低的再现性。我们的光遗传学IUGR模型将提供对血流操纵程度的更好控制，增强实验之间的再现性，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。