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

• 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
• 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

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：从罕见疾病到新范式 血管平滑肌（VSM）的兴奋性以及血管紧张性由一系列离子控制 渠道尽管这几十年的认识，和孤立的例子，主要后果的离子通道 操纵，改变VSM电兴奋性的短期和长期病理生理后果 仍然不为人所知，或调查。在这里，我提出了一系列的研究，建立在我的职位- 在博士培训中，我记录了由过度- Cantu综合征（CS）小鼠模型中VSM ATP敏感性钾（KATP）通道的活性。这些 模型提供了一个独特的机会，解剖系统机制，联系VSM低兴奋性， 心脏重塑、肺动脉高压和动脉导管未闭，以及确定 药理学阻断（磺酰脲类药物）逆转这些CV异常的潜力。由于 目前还没有针对CS的靶向治疗，这些研究具有明确的转化影响，并作为重要的预 KATP抑制剂用于CS（特别是可能用于CS相关CV）再利用的临床试验 更常见的异常-如PDA。我假设CS代表了 VSM兴奋性降低的病理生理CV后果，我将在其他遗传学研究中进行测试。 修饰的小鼠模型，其中TMEM 16 A和TRPP 1通道在平滑的细胞内被特异性敲除。 肌肉.这些研究有可能建立一个新的范式，长期的，复杂的影响， 降低VSM的电兴奋性。CS中的CV异常与高血压患者中观察到的CV异常显著重叠。 我假设VSM的电兴奋性降低是未被认识到的主要原因， 心力衰竭的易感基质，这将在这里进行测试。这个项目要求我把一个 广泛的技术，从细胞电生理学到细胞、器官的生理学方法， 整个动物的水平。结合我之前在离子通道生物物理学和电生理学方面的经验， CV生理学研究的相关技术培训和实验模型的建立 和方法，我将完全有能力进行CV系统中细胞兴奋性的未来研究， 健康和疾病。