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Functional and Molecular Changes During Development of Compensatory Hypertrophy

代偿性肥大发展过程中的功能和分子变化

基本信息

批准号：
8066313
负责人：
Kaylan Michelle Haizlip
金额：
$ 3.38万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066313
关键词：
Adrenergic Agents Affect Animal Model Bilateral Biological Assay Biopsy Calcium Cardiac Cause of Death Contractile Proteins Contracts Data Data Collection Development Diagnosis Diamond Disease Disease Progression Early Diagnosis Endoplasmic Reticulum Event Failure Feedback Frequencies Future Growth Health Health Transition Heart Heart failure Human Hypertrophy In Vitro Individual Kinetics Knowledge Mammals Microfilaments Molecular Molecular Profiling Mus Muscle Cells Myocardium Oryctolagus cuniculus Outcome Study Patients Phase Phenotype Phosphorylation Physiological Preparation Pro-Q aerosol foam Probability Process Proteins Proteomics Rattus Regulation Research Proposals Resolution Sodium-Calcium Exchanger Staging Staining method Stains System Techniques Time Tissues Western World adrenergic insight novel pointed protein prevent protein expression response treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Heart failure is the leading cause of death in the western world and is known to affect over 550,000 individuals every year. Heart failure is often preceded by hypertrophy, in which the heart wall thickens via growth of the individual myocytes. Our long-term objective is to understand the underlying molecular changes in protein expression, and the temporal resolution of this process, as this knowledge holds the key to ultimately effectively treating and preventing heart failure. These functional and molecular changes currently remain incompletely understood and are only sparsely documented in animal models larger than mice and rats. Recent data led us to hypothesize that the mechanism of developing hypertrophy prior to end-stage failure is critically dependent on the bilateral feedback between the function and expression of myofilament proteins and proteins involved in calcium handling. To understand the progression of the disease, it is thus critically important to identify the earliest changes that appear. In order to assess these temporal changes that occur during the heart's progression from normal to the hypertrophied stage we have developed a novel in vitro system. In this system we use a multi-day culture of functionally contracting multicellular preparations from the rabbit, which enable us to analyze the protein expression and contractile function and regulation throughout the progression from healthy myocardium to diseased myocardium. In aim 1 we will determine the changes in contractile function and regulation during the development of compensatory hypertrophy. In aim 2 we will elucidate the protein expression profile of these multicellular preparations during the progression from normal function to compensatory hypertrophy through the analysis of protein expression and protein phosphorylation. When combined, the temporal resolution of changes in function and protein expression and phosphorylation will give us critical insight into the mechanism of the development of hypertrophy in tissue of a large mammal under near physiological conditions. PUBLIC HEALTH RELEVANCE: The studies proposed will allow for the collection of data to enable the resolution, in a temporal manner, the changes that occur in protein expression and contractile function, as well as their interaction, during the development of hypertrophy. The outcome of the studies will provide crucial insight into the progression of this disease increasing the probability of early detection, and allow us to strategize hypothesis-driven treatment strategies for patients suffering from heart failure.

描述(申请人提供)：心力衰竭是西方世界的主要死亡原因，已知每年有超过55万人受到影响。心力衰竭通常发生在肥厚之前，在肥厚的情况下，心壁通过个别心肌细胞的生长而增厚。我们的长期目标是了解蛋白质表达的潜在分子变化，以及这一过程的时间分辨率，因为这一知识掌握着最终有效治疗和预防心力衰竭的关键。这些功能和分子变化目前仍不完全清楚，只有在比小鼠和大鼠更大的动物模型中才有很少的记录。最近的数据使我们假设，在终末期衰竭之前发生肥大的机制严重依赖于肌丝蛋白和钙处理相关蛋白的功能和表达之间的双边反馈。因此，为了了解疾病的发展，确定出现的最早的变化是至关重要的。为了评估心脏从正常到肥厚发展过程中发生的这些时间变化，我们开发了一种新的体外系统。在这个系统中，我们使用了来自兔的功能性收缩多细胞制剂的多天培养，这使得我们能够分析从健康心肌到病变心肌的整个过程中的蛋白表达和收缩功能及其调节。在目标1中，我们将确定在代偿性肥厚发展过程中收缩功能和调节的变化。在目标2中，我们将通过蛋白表达和蛋白磷酸化的分析，阐明这些多细胞制剂从正常功能到代偿性肥厚过程中的蛋白质表达谱。结合起来，功能、蛋白质表达和磷酸化变化的时间分辨率将使我们深入了解大型哺乳动物在近生理条件下组织肥大的发展机制。公共卫生相关性：拟议的研究将允许收集数据，以便能够以时间方式解决肥厚发展过程中蛋白质表达和收缩功能及其相互作用的变化。研究结果将为这种疾病的进展提供关键的洞察，增加早期发现的可能性，并使我们能够为心力衰竭患者制定假设驱动的治疗策略。