Role of altered carnitine metabolism in perinatal endothelial dysfunction

肉碱代谢改变在围产期内皮功能障碍中的作用

• 批准号: 7531878
• 负责人: Stephen M Black
• 金额: $ 19.83万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531878
• 关键词: Acyl Coenzyme A; Aging; Ants; Attention; Attenuated; Biochemical; Blood Vessels; Blood flow; Cardiopulmonary; Carnitine; Child; Congenital Heart Defects; Data; Defect; Development; Disruption; Endothelial Cells; Environment; Functional disorder; GW9662; Generations; Heat-Shock Proteins 90; Homeostasis; Hypertension; In Vitro; Inborn Errors of Metabolism; Incidence; Innovative Therapy; Lead; Levocarnitine; Live Birth; Lung; Medical; Metabolism; Mitochondria; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Newborn Infant; Operative Surgical Procedures; Pathway interactions; Perinatal; Peroxisome Proliferator-Activated Receptors; Physiological; Plasma; Post Technic; Postoperative Period; Public Health; Pulmonary Circulation; Pulmonary Hypertension; Pulmonary artery structure; Risk; Role; Role playing therapy; Secondary to; Shunt Device; Signal Transduction; Superoxides; System; Testing; Therapeutic Agents; Truncus Arteriosus; Vascular Diseases; Ventricular Septal Defects; atrioventricular septal defect; base; congenital heart disorder; hemodynamics; improved; in vivo; innovation; mitochondrial dysfunction; mortality; novel; novel diagnostics; perinatal stroke; receptor; tool

DESCRIPTION (provided by applicant): Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical treatment. Although survival for these children has improved they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular reactivity, causes significant morbidity and mortality. Our recent studies, using a lamb model of congenital heart disease and increased pulmonary blood flow, indicate that the development of endothelial dysfunction is associated with derangements in NO signaling. However, the mechanisms by which the endothelial dysfunction occurs have not been adequately resolved. Recently we have found that decreases in NO signaling correlate with altered carnitine metabolism and mitochondrial dysfunction. Thus, the Aims of this proposal are two-fold: 1) To utilize an integrated physiologic, biochemical, cellular, and molecular approach to elucidate the mechanisms underlying the disruption of carnitine metabolism in our lamb model; and 2) To utilize L-carnitine, a compound that has been used for decades to treat inborn errors of metabolism, in a novel and innovative way as a therapeutic agent for the endothelial dysfunction associated with congenital heart disease. Thus, we anticipate that the information garnered from the studies in this exploratory R21 proposal should enable us both to examine the role played by mitochondrial dysfunction in the altered vascular reactivity associated with congenital heart disease and to evaluate L-carnitine as a novel treatment strategy. The incidence of congenital heart defects in the U.S. is ~1 per 100 live births. Approximately 50% of these children require medical and/or surgical attention. The majority of defects requiring treatment are associated with increased pulmonary blood flow. This includes children born with ventricular septal defect, truncus arteriosus, or atrioventricular septal defect. Survival for children born with congenital heart defects has improved because of the development of new diagnostic tools, and advances in surgical techniques and post-operative management. However, these children continue to suffer significant morbidity and late mortality, in part because of abnormal vascular reactivity leading to endothelial dysfunction within the pulmonary circulation. PUBLIC HEALTH RELEVANCE: The factors responsible for the development of endothelial dysfunction are incompletely understood. A better understanding of the cellular and molecular mechanisms that underlie the development of endothelial dysfunction will lead to improved survival for newborns, infants, and children with congenital heart defects. Thus, the studies in this proposal evaluating a compound, L-Carnitine that has been utilized for decades to treat inborn errors of metabolism as a novel and innovative therapy for pulmonary hypertension associated with increased pulmonary blood flow have the potential to significantly impact the survival of children born with congenital heart defects.

描述（由申请人提供）：大约1%的儿童出生时患有先天性心脏缺陷，其中一半需要药物和/或手术治疗。虽然这些儿童的存活率有所提高，但他们的发病率和晚期死亡率仍然很高。这是因为他们患肺血管疾病的风险很大。事实上，即使是早期的肺内皮功能障碍，异常血管反应性，导致显着的发病率和死亡率。我们最近的研究，使用先天性心脏病和肺血流量增加的羔羊模型，表明内皮功能障碍的发展与NO信号的紊乱有关。然而，内皮功能障碍发生的机制尚未得到充分解决。最近我们发现NO信号的减少与肉毒碱代谢的改变和线粒体功能障碍有关。因此，本研究的目的有两个：1）利用综合的生理、生化、细胞和分子方法来阐明我们的羔羊模型中肉毒碱代谢中断的潜在机制;和2）利用L-肉毒碱，一种已经被用于治疗先天性代谢缺陷几十年的化合物，以新颖和创新的方式作为与先天性心脏病相关的内皮功能障碍的治疗剂。因此，我们预计，从这项探索性R21提案的研究中获得的信息应使我们能够检查线粒体功能障碍在与先天性心脏病相关的血管反应性改变中所起的作用，并评估左旋肉碱作为一种新的治疗策略。在美国，先天性心脏病的发病率约为每100例活产1例。这些儿童中约有50%需要医疗和/或手术治疗。大多数需要治疗的缺陷与肺血流量增加有关。这包括出生时患有室间隔缺损、动脉干或房室间隔缺损的儿童。由于新的诊断工具的发展，以及外科技术和术后管理的进步，先天性心脏病患儿的生存率有所提高。然而，这些儿童继续遭受显着的发病率和晚期死亡率，部分原因是异常的血管反应性导致肺循环内的内皮功能障碍。公共卫生相关性：对内皮功能障碍发生的因素尚未完全了解。更好地了解内皮功能障碍发展的细胞和分子机制将有助于改善新生儿，婴儿和先天性心脏病儿童的生存率。因此，本提案中的研究评估了一种化合物，L-肉毒碱，该化合物已被用于治疗先天性代谢缺陷数十年，作为一种新型和创新的治疗肺动脉高压与肺血流量增加有可能显着影响先天性心脏病患儿的生存。