Novel Approaches for Burn Injury Cardiac Dysfunction

治疗烧伤心脏功能障碍的新方法

• 批准号: 7534538
• 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 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534538
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Action Potentials; Animals; Anions; 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; 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; 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; 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; depression; extracellular; falls; hemodynamics; human embryonic stem cell; improved; in vivo; instrument; medical schools; mortality; novel; novel strategies; prevent; programs; protein expression; research study; 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.

烧伤损伤引发了一系列病理生理变化。尽管在烧伤损伤的临床和实验研究中，据报道，尽管有攻击性的液体复苏，左心室（LV）收缩功能的进行性下降。但是，燃烧诱导的心肌功能障碍所涉及的源或信号通路在很大程度上未知。我们小组的最新研究表明，肠道淋巴淋巴引发心肌抑郁症的肠道心肌抑制因子。此外，我们的初步研究表明，从受烧伤40％（燃烧淋巴）的大鼠中收集的肠系膜淋巴的生理相关浓度（烧伤淋巴），而不是从假烧伤的大鼠（对照淋巴）（对照淋巴）到从健康大鼠中分离出的脑肌细胞，从健康大鼠中分离出来的，导致具有动作势型与家居的重大影响有关，与异国性的ca2+ca2+ca2+ca2+ca2+ca2+ca2+ca2+ca2+。在其他初步工作中，我们发现燃烧淋巴增加了肌因素的大小，有丝分裂原激活的蛋白激酶以及培养的新生大鼠心室心肌细胞的细胞死亡，这表明燃烧创伤与肥大心脏疾病之间的常见机械联系。在此提案中，我们将利用这些发现，并提出进一步研究与烧伤诱导的心肌功能障碍有关的细胞和分子机制，以及烧伤淋巴在生理和病理生理条件中的作用。为了开始理解心肌功能改变的细胞基础，该建议着重于对心肌CA2+稳态重要的细胞机制。我们假设1）1）烧伤损伤诱导的LV功能障碍是肠系膜淋巴（淋巴）中包含的肠道衍生因子（s），以及2）离子电流和CA2+CA2+循环蛋白的变化由燃烧淋巴引起的脂肪诱导的LV功能障碍和最终的心脏失效（HF）。为了检验该假设，该赠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有价值的信息。这项研究是我们对与燃烧相关心肌功能障碍的分子机制的理解至关重要的。更好地了解分子病因和下游机制可能会改善治疗措施，以降低与烧伤损伤相关的发病率和死亡率。