Arterial 5-HT Transporter Function

动脉5-HT转运蛋白功能

基本信息

批准号：
7196512
负责人：
Stephanie W Watts
金额：
$ 32.11万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7196512
关键词：
Abbreviations Acetates Acetic Acid Acetic Acids Address Affinity Agonist Animals Anxiety Disorders Arteries Bathing Biochemistry Biological Assay Blood Pressure Blood Vessels Cardiovascular system Central Nervous System Agents Chemosensitization Contracts Cultured Cells DOCA Deoxycorticosterone Disease End Point Endothelin Endothelin-1 Fenclonine Hand High Blood Pressure Hormones Human Hydroxyindoleacetic Acid Hypertension Immunohistochemistry In Vitro Inbred SHR Rats Knowledge Laboratories Mental Depression Metabolism Methaqualone Mitogens Modeling Modification Monoamine Oxidase A Mus Muscle function Names Neurotransmitters Norepinephrine Obesity Peripheral Peripheral Resistance Phenylephrine Physiological Physiology, Other Process Rat-1 Rattus Regulation Reproduction Research Research Personnel Rodent Role Schizophrenia Selective Serotonin Reuptake Inhibitor Serotonin Serum Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes System Techniques Telemetry Testing Time Tissues Tryptophan 5-monooxygenase Vasoconstrictor Agents Work dopamine transporter experience feeding gastrointestinal hydroxyindole in vivo inhibitor/antagonist insight noradrenaline transporter programs receptor respiratory response serotonin receptor serotonin transporter tonin uptake

项目摘要

DESCRIPTION (provided by applicant): Modification of 5-hydroxytryptamine (5-HT, serotonin) concentration or receptor stimulation has resulted in treatments for depression, feeding disorders and obesity. 5-HT is also a vascular smooth muscle cell mitogen and vasoconstrictor but a significant amount of work has produced equivocal results in terms of 5-HT modifying arterial tone in vivo in the control of systemic blood pressure. Importantly, the relevance of 5-HT to peripheral arterial function has been questioned because mechanisms for arterial handing and metabolism of 5-HT are unknown. Our overall hypothesis is that the serotonin transporter (SERT) is present in peripheral arteries and has physiological consequence in arterial function. We will use an integrated set of techniques - isolated tissue baths and myographs, immunohistochemistry, Westerns, cell culture, transporter activity assays, and telemetry -- in rats and mice to address two specific Aims: Specific Aim #1: To test the hypothesis that 5-HT is taken up and released from arterial smooth muscle by SERT. We hypothesize that 5-HT is actively taken up, released and potentially stored in peripheral arteries, functions dependent on SERT. Such findings build a case for a local serotonergic system in the artery, a system which should be regulated and modifiable if physiologically important. Thus, work in this aim is directed towards understanding functional regulation of SERT and testing for the presence of components that would form a local 5-HT system: synthesis, uptake, storage and release. Specific Aim #2: To test the hypothesis that SERT modifies arterial function with physiological consequence. This aim builds on Aim 1 by studying two models in which SERT function has physiological relevance and thus enables illustration of the importance of 5-HT/SERT as it relates to modifying arterial contractility and blood pressure. The first model is the artery in which subthreshold concentrations of 5-HT potentiate arterial contraction to norepinephrine and endothelin, the second a model of hypertension. Collectively, these studies are important because they highlight the role of 5-HT in the peripheral cardiovascular system, and reveal a new functional role for SERT. Moreover, because SERT is a target for the commonly prescribed serotonin reuptake inhibitors such as ProzacZ, these studies provide potential insight into cardiovascular complications experienced by those taking SERT inhibitors.

描述（由申请人提供）：5-羟色胺（5-HT，血清素）浓度的改变或受体刺激已导致抑郁症、进食障碍和肥胖症的治疗。 5-HT 也是血管平滑肌细胞有丝分裂原和血管收缩剂，但在 5-HT 改变体内动脉张力以控制全身血压方面，大量工作产生了模棱两可的结果。重要的是，5-HT 与外周动脉功能的相关性受到质疑，因为 5-HT 的动脉输送和代谢机制尚不清楚。我们的总体假设是，血清素转运蛋白（SERT）存在于外周动脉中，并对动脉功能产生生理影响。我们将在大鼠和小鼠中使用一套集成的技术 - 分离的组织浴和肌动描记器、免疫组织化学、蛋白质印迹、细胞培养、转运蛋白活性测定和遥测 - 来解决两个特定目标：具体目标＃1：检验假设5-HT 通过 SERT 从动脉平滑肌中摄取和释放。我们假设 5-HT 被主动吸收、释放并可能储存在外周动脉中，其功能依赖于 SERT。这些发现为动脉中的局部血清素系统提供了依据，如果该系统具有生理重要性，则应该对其进行调节和修改。因此，这一目标的工作旨在了解 SERT 的功能调节，并测试形成局部 5-HT 系统的成分的存在：合成、摄取、储存和释放。具体目标#2：检验 SERT 改变动脉功能并产生生理后果的假设。这一目标建立在目标 1 的基础上，通过研究两个模型，其中 SERT 功能具有生理相关性，从而能够说明 5-HT/SERT 的重要性，因为它与改变动脉收缩力和血压有关。第一个模型是动脉，其中阈下浓度的 5-HT 会增强动脉收缩，产生去甲肾上腺素和内皮素，第二个模型是高血压模型。总的来说，这些研究很重要，因为它们强调了 5-HT 在外周心血管系统中的作用，并揭示了 SERT 的新功能作用。此外，由于 SERT 是常用的血清素再摄取抑制剂（例如 ProzacZ）的目标，这些研究为服用 SERT 抑制剂的患者所经历的心血管并发症提供了潜在的见解。