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：从罕见疾病到新范例 血管平滑肌 (VSM) 的兴奋性以及血管张力由一系列离子控制 渠道。尽管这种认识已有数十年历史，而且离子通道主要后果的孤立例子 操纵，VSM 电兴奋性改变的短期和长期病理生理学后果 仍知之甚少，或研究甚少。在这里，我提出了一系列基于我的研究成果的研究。 在博士培训中，我记录了因过度使用而引起的复杂心血管（CV）异常 坎图综合征 (CS) 小鼠模型中 VSM ATP 敏感钾 (KATP) 通道的活性。这些 模型提供了一个独特的机会来剖析将 VSM 低兴奋性与 心脏重塑、肺动脉高压和动脉导管未闭，以及确定 药物阻断（磺酰脲类药物）有可能逆转这些心血管异常。因为有 目前尚无针对 CS 的靶向治疗，这些研究具有明显的转化影响，可作为重要的预治疗 重新利用 KATP 抑制剂治疗 CS 的临床试验，特别是可能用于 CS 相关 CV 的临床试验 更普遍的异常 - 例如 PDA。我假设 CS 代表了一个定义性的例子 VSM 兴奋性降低的病理生理学 CV 后果，我将在额外的基因方面进行测试 改良小鼠模型，其中 TMEM16A 和 TRPP1 通道在平滑肌细胞中被特异性敲除 肌肉。这些研究有可能为长期、复杂的影响建立一个新的范式。 VSM 中的电兴奋性降低。 CS 中的 CV 异常与高危人群中观察到的异常重叠 输出性心力衰竭，我假设 VSM 中电兴奋性降低是一个未被认识到的原发性原因 心力衰竭的诱发因素，将在这里进行测试。这个项目需要我合并一个 广泛的技术，从细胞电生理学到细胞、器官的生理学方法 和整个动物水平。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生理学研究相关技术培训及实验模型建立 和方法，我将完全有能力在 CV 系统中开展未来的细胞兴奋性研究 健康和疾病。