Exercise, Histamine Receptors, & Vascular Health In Aging

锻炼、组胺受体、

• 批准号: 8501119
• 负责人: John R. Halliwill
• 金额: $ 56.69万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501119
• 关键词: Acute; Address; Age; Aging; Anaphylaxis; Asthma; Blood Vessels; Blood flow; CCL2 gene; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cell Degranulation; Cell Line; Cell physiology; Data; Documentation; Endothelial Cells; Exercise; Functional disorder; Future; Gene Proteins; Goals; Health; Health Benefit; Histamine; Histamine H2 Receptors; Histamine Production; Histamine Receptor; Histamine Release; Human; Hypersensitivity; Hypertension; Individual; Intervention; Intervention Studies; Knowledge; Link; Mediating; Modality; Muscle; Oxidative Stress; Pathway interactions; Patients; Peripheral; Peripheral arterial disease; Personal Satisfaction; Physical activity; Play; Population; Prevention; Production; Reactive Oxygen Species; Receptor Activation; Regional Blood Flow; Regulation; Risk Factors; Role; Signal Transduction; Signaling Molecule; Skeletal Muscle; Source; Staging; Stimulus; System; Techniques; Testing; Therapeutic; Time; Training; Up-Regulation; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular remodeling; Vasodilation; Work; aged; cardiovascular disorder prevention; cohort; design; improved; mast cell; novel; older men; older women; public health relevance; response; tumor growth

DESCRIPTION (provided by applicant): Vascular health declines with aging, and the decline is associated with peripheral artery disease. The long- term goal of this proposal is to understand the link between exercise, histamine receptors, and alterations in endothelial and vascular function so that we can exploit this link to generate novel interventions to improve or maintain vascular health in aging and treat patients with peripheral artery disease. In this context, a single bout of exercise is followed by a sustained peripheral vasodilation of the previously active skeletal muscle ("sustained post exercise vasodilation"). Histamine H1 and H2-receptors are the primary cause of sustained post exercise vasodilation. We speculate that this histaminergic pathway may play a role in improving endothelial function and stimulating vascular remodeling in response to exercise. It is unknown what signals associated with exercise activate this histaminergic pathway, or whether histamine released from mast cells or de novo production of histamine is responsible for activation of H1 and H2-receptors following exercise. It is unknown what signals related to endothelial function and vascular remodeling are dependent on activation of these receptors. Lastly, it is unclear whether the histaminergic pathway remains responsive to exercise or other stimuli in older subjects. We propose the following specific aims: 1) Identify the exercise-related signal that activates this histaminergic pathway, 2) Determine the source of histamine released by this signal, 3) Determine key endothelial and vascular regulatory signals that respond to activation of this pathway, and 4) Determine responsiveness of this pathway to exercise in older men and women. These aims are supported by the PI's prior work and will be addressed using state-of-the-art techniques in humans. Information from these studies will prove valuable on five fronts. First, these studies will expand current understanding of the vascular changes that occur following exercise. Second, we expect these studies will prove that histamine, generally associated with pathophysiological responses (e.g., asthma, allergies, anaphylaxis, and tumor growth), can play important roles in day-to-day regulation of regional blood flow related to exercise. Third, we expect these studies will identify a key pathway that contributes to the cardiovascular health benefits of lifetime physical activity by modulating critical signals for endothelial and vascular health. Fourth, we expect to show this pathway is functional in older men and women. Last, we expect these studies will identify a mechanism that can be exploited by future interventions to protect the vasculature from the age-associated decline in endothelial and vascular health and to treat peripheral artery disease. In summary, these studies will contribute to the understanding of exercise as a therapeutic modality in treatment and prevention of cardiovascular disease and set the stage for new vascular health interventions targeted at older individuals, in particular, those with conditions such as peripheral artery disease.

描述（由申请人提供）：血管健康随着年龄的增长而下降，这种下降与外周动脉疾病有关。这项提案的长期目标是了解运动、组胺受体与内皮和血管功能改变之间的联系，以便我们可以利用这一联系产生新的干预措施，以改善或维持衰老中的血管健康，并治疗外周动脉疾病患者。在这种情况下，单次运动之后是先前活跃的骨骼肌的持续外周血管舒张（“运动后持续血管舒张”）。组胺H1和H2受体是运动后持续血管舒张的主要原因。我们推测这种组胺能途径可能在改善内皮功能和刺激运动后的血管重塑方面发挥作用。目前尚不清楚与运动相关的信号激活这种组胺能通路，或者是否从肥大细胞释放的组胺或组胺的从头产生负责运动后H1和H2受体的激活。目前尚不清楚与内皮功能和血管重塑相关的信号依赖于这些受体的激活。最后，尚不清楚组胺能通路是否对老年受试者的运动或其他刺激仍有反应。我们提出了以下具体目标：1）确定激活该组胺能通路的运动相关信号，2）确定该信号释放的组胺来源，3）确定响应于该通路激活的关键内皮和血管调节信号，以及4）确定该通路对老年男性和女性运动的响应性。这些目标得到PI先前工作的支持，并将使用最先进的人类技术加以解决。这些研究提供的信息将在五个方面证明是有价值的。首先，这些研究将扩大目前对运动后血管变化的理解。其次，我们希望这些研究将证明组胺，通常与病理生理反应（例如，哮喘、变态反应、过敏反应和肿瘤生长），可以在与运动相关的局部血流的日常调节中发挥重要作用。第三，我们预计这些研究将确定一个关键途径，通过调节内皮和血管健康的关键信号，有助于终身体力活动的心血管健康益处。第四，我们希望证明这条通路在老年男性和女性中是起作用的。最后，我们希望这些研究将确定一种机制，可用于未来的干预措施，以保护血管系统免受年龄相关的内皮和血管健康下降，并治疗外周动脉疾病。总之，这些研究将有助于了解运动作为治疗和预防心血管疾病的治疗方式，并为针对老年人的新血管健康干预措施奠定基础，特别是那些患有外周动脉疾病等疾病的人。