The Serotonin Transporter in Pulmonary Arterial Hypertension

描述(申请人提供)：候选人：Kelly Chin，医学博士，德克萨斯州达拉斯的德克萨斯大学西南医学中心肺部和重症监护助理教授。她寻求对职业发展的支持，使其成为肺动脉高压领域的独立研究员。环境：将由心血管临床试验专家米尔顿·帕克博士提供指导，另外还有肺动脉高压专家刘易斯·鲁宾博士和细胞信号专家兰斯·特拉达博士提供指导。研究和职业发展：Chin博士提出了两项研究，将重点放在5-羟色胺转运体在肺动脉高压(PAH)中的作用。这两项研究将检验这一假设，即5-羟色胺转运体是肺动脉高压(PAH)患者肺压力升高的发展和持续的关键因素。第一项研究将是一项随机、双盲、安慰剂对照试验，评估用选择性5-羟色胺再摄取抑制剂氟西汀阻断5-羟色胺转运体是否会降低PAH患者的肺血管阻力。在她涉及开放标签使用氟西汀的前期工作中，Chin博士发现，与基线相比，三个月的治疗导致心脏指数(p&lt；0.05)和肺血管阻力(p=NS)的改善。在拟议的临床试验中，34名患者将随机服用安慰剂或氟西汀，为期6个月。主要终点将是肺血管阻力的变化，次要终点将包括其他血流动力学变化、运动能力、生活质量和安全性。Chin博士的第二项研究将评估使用兴奋剂和其他药物作为5-羟色胺转运体底物是否与特发性PAH有关。这将采用病例对照设计进行研究，包括70个病例和140个对照，用药将通过面对面调查确定。Chin博士之前已经证明，特发性PAH可能与甲基苯丙胺的使用有关，甲基苯丙胺是一种具有5-羟色胺转运体底物活性的兴奋剂。Chin博士建议在临床上补充这一实践培训 在统计学、药理学和肺血管生物学方面有正规课程的研究。这项工作涉及国家心肺和血液研究所的几个战略目标，包括(1)提高对健康和疾病的分子和生理基础的理解，以及(2)提高对疾病临床机制的理解，从而能够更好地预防、诊断和治疗。

DESCRIPTION (provided by applicant): Candidate: Kelly Chin, MD, is an Assistant Professor in Pulmonary and Critical Care at the University of Texas Southwestern Medical Center in Dallas, TX. She seeks support for career development to emerge as an independent investigator in the area of pulmonary arterial hypertension. Environment: Mentorship will be provided by Dr. Milton Packer, an expert in cardiovascular clinical trials, with additional mentorship from Drs. Lewis Rubin, an expert in pulmonary hypertension, and Lance Terada, an expert on cell signaling. Research and Career Development: Dr. Chin proposes two studies that will focus on the role for the serotonin transporter in pulmonary arterial hypertension (PAH). These two studies will test the hypothesis that the serotonin transporter is a key contributor to the development and persistence of elevated pulmonary pressures in patients with pulmonary arterial hypertension (PAH). The first study will be a randomized double-blind placebo controlled trial evaluating whether blockade of the serotonin transporter with fluoxetine, a selective serotonin reuptake inhibitor, will reduce pulmonary vascular resistance in patients with PAH. In her preliminary work involving open label use of fluoxetine, Dr. Chin found that three months treatment led to improvement in cardiac index (p<0.05) and pulmonary vascular resistance (p=NS) compared with baseline. In the proposed clinical trial, 34 patients will be randomized to placebo or fluoxetine for six months. The primary endpoint will be change in pulmonary vascular resistance, and secondary endpoints will include other hemodynamic changes, exercise capacity, quality of life and safety. Dr. Chin's second study will evaluate whether use of stimulants and other medications that act as serotonin transporter substrates is associated with idiopathic PAH. This will be studied using a case-control design with 70 cases and 140 controls, and medication use will be determined by in-person survey. Dr. Chin has previously shown that idiopathic PAH may be associated with use of methamphetamine, a stimulant with serotonin transporter substrate activity. Dr. Chin proposes to supplement this practical training in clinical research with formal coursework in statistics, pharmacology and pulmonary vascular biology. This work addresses several National Heart Lung and Blood Institute strategic objectives, including (1) Improving the understanding of the molecular and physiological basis of health and disease, and (2) Improving the understanding of the clinical mechanisms of disease and thereby enabling better prevention, diagnosis, and treatment.