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Optogenetic and chemogenetic regulation of uterine vascular function

子宫血管功能的光遗传学和化学遗传学调控

基本信息

批准号：
10785667
负责人：
Ramon Lorca
金额：
$ 42.9万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10785667
关键词：
Acceleration Acute Address Adverse effects Affect Agonist Altitude Animal Genetics Animal Model Animals Area Arteries Blood Vessels Blood flow Bluetooth Cardiovascular Diseases Cardiovascular system Cell membrane Cervical Child Chronic Disease Contralateral Development Drug Design Elderly Endothelial Cells Endothelium Exposure to Fetal Growth Fetal Growth Retardation Fetal Reduction Fetus Fiber Foundations G alpha q Protein G-Protein-Coupled Receptors Genetic Genetic Models Genotype Goals Growth Halorhodopsins Human Hypertension Hypoxia Impairment Implant Invaded Knowledge Life Light Longevity Measures Microfluidics Molecular Morphology Mothers Mus Muscarinic Acetylcholine Receptor Muscarinic M3 Receptor Neonatal Mortality Nitric Oxide Opsin Optics Pericytes Physiological Placenta Population Positioning Attribute Predisposition Pregnancy Pregnancy Complications Pregnancy Outcome Pregnant Uterus Proliferating Pump Regulation Relaxation Reproducibility Reproductive Health Risk Signaling Protein Smooth Muscle Smooth Muscle Myocytes Stress Techniques Testing Therapeutic Time Uterus Vagus nerve structure Vasodilation Wild Type Mouse cardiovascular disorder risk design experimental study fetal fetal blood flexibility genetic technology genetically modified cells healthy pregnancy implantation improved in vivo infant morbidity/mortality innovation internal control microbial mouse model neonatal death novel novel therapeutics optogenetics perinatal period pharmacologic pregnant prevent receptor skull implant stillbirth subcutaneous therapeutically effective therapy development tool trophoblast vascular bed

项目摘要

PROJECT SUMMARY Fetal growth restriction (FGR) increases the risk of stillbirth and neonatal death. The adverse effects of being born FGR 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 FGR. Hypoxic conditions also alter uteroplacental vascular function, reducing fetal growth, similarly to FGR. To understand the mechanisms by which an increase in uterine artery (UtA) blood flow can prevent hypoxia-dependent impaired uterine vasculature and reduced fetal growth, we propose using optogenetics and chemogenetics 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., halorhodopsin [NpHR]), which can then be selectively stimulated by light in vivo. Chemogenetics utilizes modified receptors such as the muscarinic M3 receptor (hM3Dq), which can be selectively activated by specific agonists (e.g., deschloroclozapine [DCZ]). Our goal is to develop novel and reliable murine models to prevent FGR via endothelium or smooth muscle-specific mechanisms in the UtA. To address this goal, we propose to conduct two scientific aims. In Aim 1, in mice expressing NpHR in the smooth muscle, we will address the capacity for light stimulation to vasodilate the UtA in vivo, increasing UtA blood flow and preventing FGR. Aim 2 will determine the effect of endothelium-dependent UtA vasodilation via expression of hM3Dq and its selective activation by DCZ locally applied through a microfluidic channel. Current murine models for increasing UtA blood flow in vivo require pharmacological activations that are non-tissue specific, and the timing of the activation cannot be controlled. Our optogenetic and chemogenetic models will provide better control of the degree of blood flow manipulation, enhanced reproducibility among experiments, improved selectivity of the stimulation, and the opportunity to test the timing of stimulation. This project will be the first to apply optogenetics and chemogenetics to the vasodilation of UtA in vivo. Importantly, our proposal can provide the foundation for applying optogenetics and chemogenetics to the study of other vascular beds in vivo.

项目总结