MENTORED PATIENT ORIENTED RESEARCH CAREER DEVELOPMENT AW

指导患者导向的研究职业发展 AW

基本信息

批准号：
6731981
负责人：
Steven J Garlow
金额：
$ 12.72万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-05-01 至 2006-04-30
项目状态：
已结题

项目摘要

PROPOSAL (Adapted from the applicant's abstract): Major depression is a significant independent risk factor for the development of ischemic heart disease and is a potentially lethal comorbid condition in post-myocardial infarction patients. The pathophysiology that links major depression to the occurrence of heart disease is not known. Preliminary observations indicate that platelet reactivity is increased in depression, which implies that depressed patients may be prone to thrombus formation, hence at increased risk for catastrophic cardiac events. There are considerable data indicating that the serotonergic system is altered in depression, both in the central nervous system (CNS) and in the platelets. In the periphery, the most notable and consistently replicated observation of serotonergic alteration is an increased B max for the serotonin-2A (5-HT2A) receptor on the platelets of depressed individuals. The platelet 5-HT2A receptor plays a central role in platelet reactivity and thrombus formation, and may be involved in regulating the expression of platelet specific genes in megakaryocytes, the cells from which platelets are derived. While not tested directly, the overarching hypothesis for this proposal is that major depression adversely increases platelet reactivity, which leads to increased risk of developing heart disease. The principal hypotheses that will be tested are that: 1) Platelets from depressed patients are produced in a "upregulated" state, with increased amounts of a number of transcripts that encode platelet specific genes, the result being the platelets are more reactive and prone to thrombus formation. 2) The platelet serotonergic system, in particular the 5-HT2A receptor, is altered in depression which in turn contributes to the increased platelet reactivity observed in depression, and the relevant alteration may occur in the megakaryocytes. 3) Alterations in the concentration of one or more humoral factors (interleukins, cytokines, stress hormones) orchestrate the alterations in platelet reactivity and serotonergic functioning observed in depression. Patients suffering from major depression will be recruited and their condition treated. Their platelets will be sampled before and after treatment and the amounts of transcripts that encode platelet reactivity molecules will be measured. The circulating concentration of three hormones, cortisol, interleukin-1 and interleukin-6 will be measured before and after treatment, and correlated to platelet reactivity.

提案（改编自申请人的摘要）：重度抑郁症是一种缺血性心脏病发生的重要独立危险因素疾病，并且是心肌病后潜在致命的合并症梗塞患者。将重度抑郁症与心脏病的发生尚不清楚。初步观察表明抑郁症时血小板反应性增加，这意味着抑郁症患者可能容易形成血栓，因此风险增加灾难性的心脏事件。有大量数据表明抑郁症时，中枢神经系统的血清素能系统发生改变系统（CNS）和血小板。在外围，最引人注目的是持续重复观察血清素能改变会增加抑郁症患者血小板上血清素 2A (5-HT2A) 受体的 B max 个人。血小板5-HT2A受体在血小板中起核心作用反应性和血栓形成，并可能参与调节巨核细胞中血小板特异性基因的表达，这些细胞血小板衍生而来。虽然没有直接测试，但总体假设该提议的理由是，重度抑郁症会不利地增加血小板反应性，导致患心脏病的风险增加。这将要检验的主要假设是： 1) 血小板抑郁症患者处于“上调”状态，编码血小板特异性基因的大量转录本，结果是血小板反应性更强，更容易形成血栓。 2) 血小板血清素能系统，特别是 5-HT2A 受体，是抑郁症时改变，进而导致血小板增加在抑郁症中观察到的反应性，相关的改变可能发生在巨核细胞。 3) 改变一种或多种物质的浓度体液因素（白细胞介素、细胞因子、应激激素）协调观察到血小板反应性和血清素能功能的改变沮丧。将招募患有重度抑郁症的患者并他们的病情得到了治疗。他们的血小板将在之前和之后被采样治疗和编码血小板反应性的转录物数量将测量分子。三种激素的循环浓度，前后分别测量皮质醇、白细胞介素 1 和白细胞介素 6 治疗，并与血小板反应性相关。