Neuromechanical basis of baroreceptor function

压力感受器功能的神经力学基础

• 批准号: 7528413
• 负责人: JOHN H SCHILD
• 金额: $ 38.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528413
• 关键词: Accounting; Acute; Age; Aging; Anatomy; Aorta; Arteries; Atherosclerosis; Automobile Driving; Baroreflex; Basement membrane; Biomedical Engineering; Blood Pressure; Blood Vessels; Brain; Cardiovascular Pathology; Cardiovascular Physiology; Cellular Mechanotransduction; Chronic; Clinical; Code; Collagen; Collagen Fiber; Companions; Complement; Complex; Computer Simulation; Computers; Computing Methodologies; Data; Disease; Elastin; Electron Microscopy; Electrons; Event; Face; Fiber; Free Nerve Ending; Functional disorder; Health; Heart; Heart Rate; Hypertension; Impairment; In Vitro; Ion Channel; Label; Lead; Measurement; Mechanics; Mechanoreceptors; Mediating; Membrane; Methodology; Microanatomy; Microscopic; Microscopy; Modification; Molecular; Nerve Endings; Neuroanatomy; Neuromechanics; Neurons; Oxidative Stress; Pathology; Physicians; Physiological; Positioning Attribute; Pressoreceptors; Process; Property; Rattus; Regional Anatomy; Relative (related person); Research; Resolution; Risk; Stretching; Structure-Activity Relationship; Subgroup; Syncope; Testing; Time; Tissues; Work; age related; autocrine; autonomic reflex; base; cholinergic; clinically relevant; clinically significant; computer studies; conditioning; density; extracellular; heart function; hemodynamics; immunoreactivity; insight; neuromechanism; neuronal cell body; neuroregulation; paracrine; pressure; protein expression; public health relevance; relating to nervous system; response; sensor; spatial integration; sudden cardiac death; vector

DESCRIPTION (provided by applicant): Arterial baroreceptors (BR) are essential for reliable neural control of heart rate and blood pressure. The data quantifying the properties of these pressoreceptors and the reflexogenic consequences of BR function and dysfunction are extensive. Experimental interpretations of baroreflex dysfunction and cardiovascular pathologies such as neurally mediated syncope, dysrhythmias and hypertension are of significant clinical importance. Age related changes in arterial wall properties strongly correlate with cardiovagal baroreflex impairment, increased levels of blood pressure variability, an impaired ability to respond to acute hemodynamic challenges and increased risk of sudden cardiac death (Monahan, 2007). The BR sensor itself represents an essential functional intersection across these diverse pathologies and yet a clarifying explanation of the transduction machinery is lacking. Our working hypothesis is that the microanatomy, extracellular tissue matrix, excitable neural membrane of the BR terminal complex and regional arterial wall tissues all make functionally distinct contributions to the spatial integration and transduction of localized micromechanical forces arising from arterial pressure dynamics. Our specific aims center upon the neuromechanical properties of myelinated and unmyelinated rat aortic BR as these are accessible for both micro- and macroscopic study using three complementary methodologies: 1) confocal, electron and fluorescent microscopy in conjunction with immunohistochemical labeling of protein expression within, and the tissue constructs that circumscribe, the BR terminal ending, 2) extracellular recording of aortic BR fiber discharge in response to computer controlled pressure loading of the arterial wall and 3) synthesis of these disparate microscopy and biophysical data into comprehensive computational models of the neural and micromechanical mechanisms of mechanosensory transduction that are inaccessible for direct testing and measurement. Our preliminary results illustrate: 1) essential differences between the topological distribution of molecularly identified ion channels along the ultrastructure of BR terminals with myelinated and unmyelinated fibers, 2) a minimum complement of the ion channels expressed at the cell body of BR neurons may underlie the neurogenic mechanisms of mechanotransduction and 3) that these ionic mechanisms contribute to, but cannot entirely account for, such dynamic properties as adaptation, hysteresis and resetting of discharge threshold. This combined experimental and computational strategy is producing a more biophysical understanding of the structure-function relationships associated with BR afferents relative to the basement membrane about the terminal ending, the elastin and collagen fibers within the surrounding tissue matrix as well as the neuro-integrative processes of mechanotransduction. As we recently demonstrated (Feng et al., 2007), this integrative approach can lead to new insights concerning acute cardiovascular pathologies that are well known to invoke autonomic reflexes through activation of arterial mechanoreceptors. PUBLIC HEALTH RELEVANCE: In order for the brain to properly control the heart it must continually receive information concerning blood pressure and heart rate. This application involves experimental bioengineering research related to the arterial pressure sensors (baroreceptors) that provide this critically important information to the brain. A more detailed understanding of how these sensors normally work and adapt to short and long term changes in blood pressure, heart rate and the condition of the arteries (e.g. with aging) will help physicians better manage heart function under conditions of health and disease.

描述(由申请人提供)：动脉压力感受器(BR)对于可靠的心率和血压的神经控制是必不可少的。量化这些压力感受器的特性以及BR功能和功能障碍的反射性后果的数据是广泛的。压力感受性反射功能障碍和心血管疾病的实验解释，如神经介导性晕厥、心律失常和高血压具有重要的临床意义。动脉壁特性的年龄相关变化与心脏迷走神经压力感受性反射受损、血压变异性水平升高、对急性血流动力学挑战的反应能力受损以及心源性猝死风险的增加密切相关(Monahan，2007)。BR传感器本身代表了这些不同病理过程中的一个重要的功能交叉点，但对转导机制缺乏一个明确的解释。我们的工作假设是，BR终末复合体的显微解剖、细胞外组织基质、可兴奋的神经膜和局部动脉壁组织在动脉压动力学产生的局部微机械力的空间整合和传递中都做出了不同的功能贡献。我们的具体目标是研究有髓和无髓大鼠主动脉BR的神经力学特性，因为这些都可以使用三种互补的方法进行微观和宏观研究：1)共聚焦显微镜、电子显微镜和荧光显微镜结合免疫组织化学标记BR末端内的蛋白表达和限制BR末端的组织结构；2)响应于计算机控制的动脉壁压力负荷，BR纤维放电的细胞外记录；3)将这些不同的显微镜和生物物理数据合成到无法直接测试和测量的机械传感转导的神经和微观机械机制的综合计算模型中。我们的初步结果表明：1)分子识别的离子通道在有髓纤维和无髓纤维的BR终末超微结构上的拓扑分布存在本质差异；2)在BR神经元细胞体表达的离子通道的极少量互补可能是机械信号转导的神经发生机制的基础；3)这些离子机制有助于但不能完全解释适应、滞后和放电阈值重置等动态特性。这种实验和计算相结合的策略正在产生对BR传入与末端周围基底膜、周围组织基质中的弹性蛋白和胶原纤维以及机械转导的神经整合过程相关的结构-功能关系的更多生物物理理解。正如我们最近展示的(冯等人，2007年)，这种综合方法可以导致对急性心血管病理的新见解，众所周知，这些急性心血管病理通过激活动脉机械感受器来激发自主神经反射。与公共健康相关：为了让大脑正确控制心脏，它必须不断地接收有关血压和心率的信息。这一应用涉及与动脉压力传感器(压力感受器)相关的实验生物工程研究，这些传感器为大脑提供这一至关重要的信息。更详细地了解这些传感器如何正常工作并适应血压、心率和动脉状况的短期和长期变化(例如，随着年龄的增长)，将有助于医生在健康和疾病条件下更好地管理心脏功能。