Immunoregulation by DHEA:To Prevent Cardiac Dysfunction

DHEA 的免疫调节：预防心脏功能障碍

• 批准号: 7292287
• 负责人: RONALD Ross WATSON
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292287
• 关键词: Acquired Immunodeficiency Syndrome; Adoptive Transfer; Adrenal Glands; Affect; Age; Aging; Aging-Related Process; Attenuated; CD4 Positive T Lymphocytes; Carbohydrates; Cardiac; Cardiovascular system; Cells; Clinical; Collagen; Collagen Type I; Consumption; Data; Dehydroepiandrosterone Sulfate; Development; Diastolic heart failure; Diet; Dilated Cardiomyopathy; Disease; Disease regression; Endocrine; Enzymes; Extracellular Matrix; Family; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Gene Structure; HIV; Hand; Heart; Heart Diseases; Heart failure; Human; Hypertension; Immune; Immune System Diseases; Immune system; In Vitro; Incubated; Individual; Injury; Left; Lymphocyte; Lymphocyte Function; Mediating; Metabolic syndrome; Metalloproteases; Modeling; Modification; Murine Acquired Immunodeficiency Syndrome; Mus; Myocardial; Pathway interactions; Phenotype; Placebos; Process; Production; Property; Protein-Lysine 6-Oxidase; Regulation; Reporting; Research; Resistance; Retroviridae; Risk Factors; Rodent Model; Role; Serum; Structure; Supplementation; Systolic heart failure; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Ventricular; Ventricular Dysfunction; Ventricular Function; Water; Wild Type Mouse; Work; acquired immunodeficiency; age related; aged; base; clinically relevant; concept; crosslink; cytokine; dehydroepiandrosterone; drinking water; feeding; immune function; immunoregulation; immunosenescence; in vitro Model; in vivo; interstitial; middle age; prevent; restoration; steroid hormone

DESCRIPTION (provided by applicant): This proposal will examine the mechanism of action of the CAM agent, dehydroepiandrosterone-sulfate (DHEAS) on modification of cardiac ventricular function via regulation of the adaptive immune function. Established rodent models of clinical risk factors that result in cardiac ventricular dysfunction will be studied, namely: advancing middle age and metabolic syndrome. Moreover, aging and metabolic syndrome are predictors of heart failure (HF) independent of other established risk factors, underscoring the need for the development of CAM therapeutics. Currently, there are 26 approved therapeutics for systolic HF- none of which reverse the progression of the diastolic HF. Our data suggest that immune modulation of lymphocyte function has direct effects on the cardiac structure and function in vivo and cardiac fibroblast functions in vitro. Our data support the concept that both aging and metabolic syndrome induce immune dysfunction and ventricular dysfunction. The key objective is to demonstrate that through the immunomodulatory properties of DHEAS ventricular dysfunction will be prevented or reversed by regulation of immune dysfunction. More specifically middle aged as well as young mice fed a high-fat high-simple carbohydrate diet producing a metabolic syndrome have significantly dilated ventricular function with a dominance of T helper (TH)2 lymphocyte function. DHEAS promotes TH1 lymphocyte function which should reverse TH2 polarization induced by age and/or metabolic syndrome, thereby halting the progression or inducing regression of the dilated ventricular function. The specific aims will associate lymphocyte function with ventricular gene, structure and function using in vivo and in vitro models to demonstrate the effects of immune regulation by DHEAS on cardiac structure and function. We will also exploit our established model of CD4+ lymphocyte adoptive transfer to naive SCID mice which are without CD4+ lymphocytes. This will demonstrate a direct effect of DHEAS modified CD4+ lymphocytes on cardiac gene, structure, and function. As DHEAS regulates the TH1 and TH2 phenotype CD4+ lymphocytes its immunoregulatory actions on cardiac structure and functions will be defined. The concepts gained from these studies will provide a basis for use of DHEAS as a CAM therapeutic to retard development and stimulate regression of dilated ventricular dysfunction associated with aging and/or metabolic syndrome. Dehydroepiandrosterone (DHEA), a CAM agent, is part of a family of adrenal steroid hormones with significant activity in regulating or "normalizing" dysfunctional immune systems. Recently we demonstrated that dysregulation of CD4+ lymphocytes profoundly and adversely altered diastolic function and cardiac extracellular matrix (ECM) composition. We have also shown that CD4+lymphocyte secretory products have a direct effect on primary cardiac fibroblast function in vitro. Our data support the hypothesis that polarization ofCD4+ lymphocytes to TH2 (T-helper 2) phenotype results in dilated cardiomyopathy (DCM). Our recent preliminary study found that DHEAS (DHEA-sulfate) reversed left ventricular stiffness and fibrosis due to aging, hypothesizing that such cardiac remodeling can be explained by DHEAS' known restoration of immunoregulatory activity in the aged mouse. This proposal will examine the role of the CAM agent, DHEAS in ameliorating heart disease through lymphocyte regulation thereby retarding cardiac remodeling and dysfunction associated with age or diet.

描述(由申请人提供)：本提案将研究CAM试剂脱氢表雄酮-硫酸酯(DHEAS)通过调节适应性免疫功能来改变心功能的作用机制。将研究已建立的导致心室性功能障碍的临床危险因素的啮齿动物模型，即：步入中年和代谢综合征。此外，衰老和代谢综合征是心力衰竭(HF)的预测因子，独立于其他已确立的风险因素，这突显了发展CAM疗法的必要性。目前，已批准的治疗收缩期心衰的药物有26种--没有一种能逆转舒张期心力衰竭的进程。提示淋巴细胞功能的免疫调节直接影响体内心脏的结构和功能以及体外心脏成纤维细胞的功能。我们的数据支持衰老和代谢综合征都会导致免疫功能障碍和心功能障碍的概念。主要目的是证明通过DHEAS的免疫调节特性，可以通过调节免疫功能障碍来预防或逆转心功能障碍。更具体地说，中年和年轻小鼠喂食高脂肪、高简单碳水化合物饮食，产生代谢综合征，显着扩大了以T辅助(TH)2淋巴细胞功能为主的心脏功能。DHEAS促进TH1淋巴细胞功能，从而逆转由年龄和/或代谢综合征引起的TH2极化，从而阻止或诱导扩大的心功能的进展或退化。具体目的是将淋巴细胞功能与心脏基因、结构和功能联系起来，利用体内和体外模型来展示DHEAS对心脏结构和功能的免疫调节作用。我们还将利用我们建立的CD4+淋巴细胞过继转移模型，将其转移到没有CD4+淋巴细胞的幼年SCID小鼠。这将证明DHEAS修饰的CD4+淋巴细胞对心脏基因、结构和功能的直接影响。当DHEAS调节TH1和TH2表型的CD4+淋巴细胞时，其对心脏结构和功能的免疫调节作用将被明确。从这些研究中获得的概念将为使用DHEAS作为一种CAM疗法提供基础，以延缓与衰老和/或代谢综合征相关的扩张性心功能障碍的发展并刺激其消退。脱氢表雄酮(DHEA)是一种CAM制剂，是肾上腺类固醇激素家族的一部分，在调节或“正常化”功能失调的免疫系统方面具有显著的活性。最近我们发现，CD4+淋巴细胞的失调会对心脏的舒张期功能和心脏细胞外基质(ECM)成分产生严重的不利影响。我们还表明，在体外，CD4+淋巴细胞分泌产物对原代心脏成纤维细胞的功能有直接影响。我们的数据支持这一假设，即CD4+淋巴细胞向TH2(T-helper 2)表型的极化导致扩张型心肌病(DCM)。我们最近的初步研究发现，DHEAS(DHEA-硫酸盐)逆转了由于衰老引起的左心室僵硬和纤维化，假设这种心脏重构可以通过DHEAS已知恢复老年小鼠的免疫调节活动来解释。这项提案将研究CAM试剂DHEAS通过调节淋巴细胞从而延缓心脏重构和与年龄或饮食相关的功能障碍来改善心脏病的作用。