Arterial 5-HT Transporter Function

动脉5-HT转运蛋白功能

基本信息

批准号：
7585316
负责人：
Stephanie W Watts
金额：
$ 32.54万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7585316
关键词：
Abbreviations Acetates Acetic Acids Address Affinity Agonist Animals Anxiety Disorders Arteries Bathing Biochemistry Biological Assay Blood Pressure Blood Vessels Cardiovascular system Cell Culture Techniques Central Nervous System Agents Chemosensitization Contracts DOCA Deoxycorticosterone Disease Endothelin Endothelin-1 Fenclonine Hand Hormones Human Hydroxyindoleacetic Acid Hypertension Immunohistochemistry In Vitro Inbred SHR Rats Knowledge Laboratories Metabolism Methaqualone Mitogens Modeling Modification Monoamine Oxidase A Mus Muscle Muscle function Names Neurotransmitters Norepinephrine Obesity Peripheral Peripheral Resistance Phenylephrine Physiological Physiology 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 depression 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

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 subthreshpld 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 Prozac¿, these studies provide potential insight into cardiovascular complications experienced by those taking SERT inhibitors.

5-羟色胺（5-HT，血清素）浓度的改变或受体刺激具有导致抑郁症、进食障碍和肥胖症的治疗。5-HT 也是一种血管药物。平滑肌细胞有丝分裂原和血管收缩剂，但已产生大量工作 5-HT 改变体内动脉张力以控制全身血液的结果不明确重要的是，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总体上尚不清楚。假设是血清素转运蛋白（SERT）存在于外周动脉中并且具有我们将使用一套综合技术对动脉功能产生生理影响 - 分离组织浴和肌动描记器、免疫组织化学、Western、细胞培养、在大鼠和小鼠中进行转运蛋白活性测定和遥测，以实现两个特定目标：具体目标#1：检验动脉吸收和释放 5-HT 的假设我们通过 SERT 发现平滑肌积极地吸收、释放和释放 5-HT。这些发现可能储存在外周动脉中，其功能依赖于 SERT。动脉中局部血清素能系统的情况，该系统应该受到调节和如果生理上重要的话是可以修改的，因此，这一目标的工作旨在理解。 SERT 的功能调节和测试组成部分的存在局部5-HT系统：合成、摄取、储存和释放。具体目标 #2：检验 SERT 改变动脉功能的假设该目标建立在目标 1 的基础上，通过研究 SERT 的两个模型。功能具有生理相关性，因此可以说明功能的重要性 5-HT/SERT，因为它与改变动脉收缩力和血压有关。阈下浓度的 5-HT 会增强动脉收缩去甲肾上腺素和内皮素是第二种高血压模型。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，并揭示 SERT 的新功能作用。因为 SERT 是常用血清素再摄取抑制剂的目标，例如百忧解?? ，这些研究提供了对所经历的心血管并发症的潜在见解那些服用 SERT 抑制剂的人。