Electrical excitability in vascular smooth muscle: from rare disease to new paradigms

血管平滑肌的电兴奋性：从罕见疾病到新范例

基本信息

批准号：
10578997
负责人：
Conor McClenaghan
金额：
$ 24.9万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578997
关键词：
ABCC9 gene Address Affect Angiotensins Animals Behavior Biophysics Blood Pressure Blood Vessels CRSP3 gene Cantu syndrome Cardiac Cardiac Myocytes Cardiac Output Cardiovascular Abnormalities Cardiovascular Diseases Cardiovascular Pathology Cardiovascular Physiology Cardiovascular system Cell membrane Characteristics Charge Chronic Clinical Complex Congenital Abnormality Data Disease Dominant-Negative Mutation Down-Regulation Drug usage Electrophysiology (science)Etiology Exhibits Experimental Models Functional disorder Future Genes Glyburide Health Heart Abnormalities Heart Hypertrophy Heart failure High Cardiac Output Human Hypoxia Investigation Ion Channel Ion Channel Gating Ions Knock-in Knock-out Link Long-Term Effects Lung Medical Mentors Modeling Molecular Movement Mus Muscle Cells Mutation Neonatal Non-Insulin-Dependent Diabetes Mellitus Organ Pancreas Patent Ductus Arteriosus Pathologic Peripheral Resistance Pharmaceutical Preparations Pharmacology Phase Phenotype Physiological Physiology Potassium Preclinical Testing Premature Infant Protein Isoforms Pulmonary Hypertension Rare Diseases Renin Research Secondary to Series Signal Transduction Smooth Muscle Sulfonylurea Compounds Techniques Testing Tissues Training Transgenic Mice Vascular Smooth Muscle blood pressure regulation cardiovascular health career disease-causing mutation efficacy testing experience gain of function gain of function mutation heart function in vivo evaluation inhibitor insight mouse model mutant novel patient population post-doctoral training response targeted treatment therapeutic target tool translational impact translational study vascular abnormality

项目摘要

Electrical excitability in vascular smooth muscle: from rare disease to new paradigms Excitability of vascular smooth muscle (VSM), and hence vascular tone, is controlled by a constellation of ion channels. Despite this decades-old recognition, and isolated examples of primary consequences of ion channel manipulation, both short- and long-term pathophysiological consequences of altered VSM electrical excitability remain poorly understood, or investigated. Here, I propose a series of studies which build from my post- doctoral training in which I have documented complex cardiovascular (CV) abnormalities arising from over- activity of VSM ATP-sensitive potassium (KATP) channels in mouse models of Cantu Syndrome (CS). These models provide a unique opportunity to dissect the systemic mechanisms that link VSM hypo-excitability to cardiac remodeling, pulmonary hypertension, and patent ductus arteriosus, as well as to determine the potential for pharmacological blockade (with sulfonylurea drugs) to reverse these CV abnormalities. As there is currently no targeted therapy for CS, these studies have clear translational impact and serve as a vital pre- clinical test for the repurposing of KATP inhibitors for CS, specifically, and potentially for CS-related CV abnormalities more generally - such as PDA. I hypothesize that CS represents a defining example of the pathophysiological CV consequences of decreased VSM excitability, which I will test in additional genetically modified mouse models in which TMEM16A and TRPP1 channels are specifically knocked-out in smooth muscle. These studies have the potential to establish a new paradigm for the long-term, complex effects of decreased electrical excitability in VSM. CV abnormalities in CS overlap strikingly with those observed in high- output heart failure and I hypothesize that decreased electrical excitability in VSM is an unrecognized primary predisposing substrate for cardiac failure, which will be tested here. This project requires me to incorporate a wide range of techniques, from cellular electrophysiology, to physiological approaches at the cellular, organ and whole animal level. By combining my prior experience in ion channel biophysics and electrophysiology, training in relevant techniques for the study of CV physiology, and the establishment of experimental models and approaches, I will be fully equipped to carry out future studies of cellular excitability in the CV system in health and disease.

血管平滑肌的电兴奋性：从稀有疾病到新范式血管平滑肌（VSM）的兴奋性及其血管张力的兴奋性由离子组控制频道。尽管有数十年历史的识别和离子通道主要后果的孤立示例操纵，包括改变VSM电兴奋性的短期和长期病理生理后果保持不当理解或调查。在这里，我提出了一系列研究，这些研究是根据我的帖子进行的我已经记录了我记录的复杂心血管（CV）异常的培训 VSM ATP敏感钾（KATP）通道的活性在CANTU综合征模型（CS）中。这些模型提供了一个独特的机会，可以剖析将VSM缺乏效果联系起来的系统机制心脏重塑，肺动脉高压和专利管道动脉静脉曲张，并确定药理阻滞的潜力（使用磺酰脲药物）扭转了这些CV异常。如有目前尚无针对CS的针对性治疗，这些研究具有明显的翻译影响，并成为至关重要的预期。针对CS的KATP抑制剂重新利用的临床测试，具体是与CS相关的CV的临床测试更普遍的异常 - 例如PDA。我假设CS代表了 VSM兴奋性降低的病理生理简历后果，我将在其他遗传学上进行测试 TMEM16A和TRPP1通道的改良鼠标模型在平滑中专门敲出肌肉。这些研究有可能建立一个新的范式，以实现长期的复杂影响 VSM中的电兴奋性降低。 CS中的CV异常与高中观察到的CV重叠输出心力衰竭，我假设VSM中的电兴奋性降低是未识别的主要原理易感心力衰竭的底物，将在此处进行测试。这个项目要求我合并从细胞电生理学到细胞器官的生理方法的广泛技术范围和整个动物水平。通过结合我先前在离子通道生物物理学和电生理学方面的经验，相关技术培训CV生理学和实验模型的建立和方法，我将有足够的能力进行对CV系统中细胞兴奋性的未来研究健康与疾病。