Novel Approaches for Burn Injury Cardiac Dysfunction

治疗烧伤心脏功能障碍的新方法

• 批准号: 7327812
• 负责人: ATSUKO YATANI
• 金额: $ 37.75万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327812
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Action Potentials; Animals; Anions; Appendix; Applications Grants; Authorization documentation; Biological; Biological Assay; Biology; Blood Circulation; Burn Trauma; Burn injury; Caliber; Cardiac; Cardiac Myocytes; Cell Death; Cell Line; Cell Size; Cell Survival; Cell physiology; Cells; Cellular biology; Cessation of life; Chromatography; Clinical; Complement component C1s; Complex; Condition; Conscious; Coupling; Data; Development; Disclosure; Doctor of Medicine; Doctor of Philosophy; Duct (organ) structure; Electrophysiology (science); Etiology; Face; Functional disorder; Genes; Genomics; Heart; Heart Diseases; Heart Rate; Heart failure; Homeostasis; Human Resources; In Vitro; Instruction; Intestines; Ion Channel; Last Name; Lead; Left; Left Ventricular Dysfunction; Left Ventricular Function; Ligation; Link; Liquid substance; Lymph; MAPK14 gene; Measures; Mental Depression; Mesentery; Messenger RNA; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Molecular Medicine; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Depressant Factor; Myocardial dysfunction; Names; Neonatal; New Jersey; Numbers; Operative Surgical Procedures; Pharmaceutical Preparations; Physiologic intraventricular pressure; Physiological; Play; Preventive; Principal Investigator; Printing; Property; Protein Chemistry; Proteins; Pump; Rat-1; Rattus; Registries; Reporting; Research; Research Personnel; Research Project Grants; Resuscitation; Role; Secondary to; Series; Signal Pathway; Signal Transduction; Source; Stress; Testing; Therapeutic; Time; Venous; Ventricular; Work; base; cell growth; channel blockers; extracellular; falls; hemodynamics; human embryonic stem cell; improved; in vivo; instrument; medical schools; mortality; novel; novel strategies; prevent; programs; protein expression; research study; size; voltage clamp

Burn injury initiates a series of pathophysiological changes. A progressive fall in left ventricular (LV) contractile function despite aggressive fluid resuscitation has been reported in both clinical and experimental studies of burn injury. However, the source(s) or the signaling pathways involved in burn-induced myocardial dysfunction remain largely unknown. Recent studies from our group indicated that gut-derived myocardial depressant factors carried in intestinal lymph trigger myocardial contractile depression. In addition, our preliminary studies demonstrated that the physiologically relevant concentrations of mesenteric lymph collected from rats receiving 40 % burn injury (burn lymph), but not lymph from sham-burned rats (control lymph), to ventricular myocytes isolated from healthy rats leads to a significant alterations in action potential duration associated with disturbed Ca2+homeostasis. In other preliminary work, we have found that burn lymph increases myocyte size, mitogen-activated protein kinases and cell death of cultured neonatal rat ventricular myocytes after 24 hrs incubation, suggesting a common mechanistic link between burn trauma and hypertrophic heart disease. In this proposal, we will capitalize on these discoveries and propose to further investigate the cellular and molecular mechanisms involved in burn-induced myocardial dysfunction and the roles of burn lymph in physiological and pathophysiological conditions. To begin understanding the cellular basis for altered myocardial function, this proposal focuses on cellular mechanisms important for myocardial Ca2+ homeostasis. We hypothesize that 1) burn injury-induced LV dysfunction is secondary to gut-derived factor(s) contained in mesenteric lymph (burn lymph), and 2) changes in ionic currents and Ca2+-cycling proteins caused by burn lymph are involved in burn-induced LV dysfunction and ultimately to heart failure (HF). To test the hypothesis, this grant proposal also includes genomics and protein chemistry to elucidate valuable information in the heart after burn injury. This research is fundamental to our understanding of molecular mechanisms of burn-related myocardial dysfunction. A better understanding of molecular etiology and downstream mechanisms could lead to improved therapeutic measures to reduce the morbidity and mortality associated with burn injury.

烧伤引发一系列病理生理变化。在烧伤的临床和实验研究中，尽管进行了积极的液体复苏，但左心室（LV）收缩功能仍进行性下降。然而，烧伤引起的心肌功能障碍的来源或信号通路仍然很大程度上未知。我们课题组最近的研究表明，肠淋巴中携带的肠源性心肌抑制因子会引发心肌收缩抑制。此外，我们的初步研究表明，从接受 40% 烧伤的大鼠中收集的肠系膜淋巴液（烧伤淋巴液），而不是从假烧伤大鼠中收集的淋巴液（对照淋巴液），与从健康大鼠中分离的心室肌细胞的生理相关浓度导致与 Ca2+ 稳态紊乱相关的动作电位持续时间的显着变化。在其他初步工作中，我们发现烧伤淋巴液会增加培养的新生大鼠心室肌细胞在培养24小时后的心肌细胞大小、丝裂原激活蛋白激酶和细胞死亡，这表明烧伤创伤和肥厚性心脏病之间存在共同的机制联系。在本提案中，我们将利用这些发现，并建议进一步研究烧伤引起的心肌功能障碍的细胞和分子机制以及烧伤淋巴在生理和病理生理条件中的作用。为了开始了解心肌功能改变的细胞基础，该提案重点关注对心肌 Ca2+ 稳态重要的细胞机制。我们假设 1) 烧伤引起的左心室功能障碍继发于肠系膜淋巴液（烧伤淋巴液）中所含的肠源性因子，2) 烧伤淋巴液引起的离子电流和 Ca2+ 循环蛋白的变化与烧伤有关-引起左心室功能障碍并最终导致心力衰竭（HF）。为了检验这一假设，这项拨款提案还包括基因组学和蛋白质化学，以阐明烧伤后心脏中的有价值的信息。这项研究对于我们理解烧伤相关心肌功能障碍的分子机制至关重要。更好地了解分子病因学和下游机制可以改进治疗措施，以降低烧伤相关的发病率和死亡率。