Tissue Engineering Strategies: Effects on Valvular Interstitial Cell Metabolism

组织工程策略：对瓣膜间质细胞代谢的影响

基本信息

批准号：
8241919
负责人：
KATHRYN JANE GRANDE-ALLEN
金额：
$ 7.63万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8241919
关键词：
Address Adhesions Adult Affect American Anabolism Anisotropy Behavior Biology Biomedical Engineering Blood Vessels Cardiac Cardiovascular system Cell Communication Cell Culture Techniques Cells Cellular biology Characteristics Chemical Stimulation Complement Congenital Abnormality Data Development Diabetes Mellitus Diffusion Dilatation - action Disease Disease Progression Doctor of Philosophy Engineering Environment Explosion Extracellular Matrix Extracellular Matrix Proteins Fatty Acids Feasibility Studies Frequencies Future Gene Expression Glucose Glycolysis Glycosaminoglycans Goals Heart Valve Diseases Heart Valves Hospitalization Hyaluronan Hypoxia In Vitro Incidence Infection Injury Investigation Knowledge Measures Mechanical Stimulation Mechanics Mediating Medical Metabolic Metabolic syndrome Metabolism Methods Microarray Analysis Myocardium Obesity Operative Surgical Procedures Oxygen Oxygen Consumption Pattern Perfusion Phenotype Prevention Principal Investigator Process Production Proteins Publications Research Research Methodology Research Personnel Role Scientist Signal Transduction Smooth Muscle Myocytes Staging Stimulus Stress Stretching Testing Therapeutic Tissue Engineering Tissues Translating Work aortic valve disorder base cell type cytokine effective therapy emergency service responder fatty acid metabolism fatty acid oxidation flexibility in vivo infancy interstitial cell metabolic abnormality assessment novel nutrient metabolism oxidation public health relevance repaired response stressor success sugar tissue support frame tool

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY Principal Investigator: Kathryn Jane Grande-Allen, Ph.D. Heart valve disease mandates hospitalization for almost 100,000 Americans every year. Although some of the initial causes of valve disease are well recognized, the intermediate cell-mediated disease mechanisms are largely unknown. The only effective treatment for most valve diseases is surgical repair or replacement; there are no medical or therapeutic treatments for the prevention or amelioration of valve disease. The drive to dissect potential disease mechanisms and develop new medical therapies has invigorated research in valve biology. This field is in its infancy, but has nonetheless has witnessed many recent findings about contractile, synthetic, cell communication, adhesion, and signaling characteristics of valvular interstitial cells (VICs), especially as they relate to the tissue engineering of valves and the development of calcific aortic valve disease. Nonetheless, there has been scant investigation into the metabolism of valve cells. Although recent publications have addressed how oxygen diffusion and perfusion affects valve cells and tissue engineered valves, the topic of valvular cell metabolism remains largely unaddressed. Cells within normal adult valves maintain quiescence (even within such a mechanically active tissue), but show the capacity to become activated and alter their phenotype/behavior in response to various injury or disease conditions. This activation process is quite poorly characterized, leading to several questions about the fundamental metabolic rates of VICs under these quiescent and activated conditions. It is also unknown how this metabolic rate is influenced by the environment of the cell, meaning its pericellular matrix and level of mechanical or chemical stimulation. These issues are very important given the use of exogenous stimuli in the development of tissue engineered valves, and the roles of these factors in valve remodeling and disease progression. Indeed, metabolism is recognized as the first responder to environmental stresses for most cell types. To address these questions, this research proposes to determine the fundamental metabolic rates of VICs (Aim 1). The following 2 aims will examine the effect of cytokine and hypoxic stimulation (Aim 2) and mechanical stretch (Aim 3) on metabolic rates and metabolic gene expression by VICs. This research is significant because it will provide new and fundamental information about the metabolic rates of VICs under basal and stressed culture conditions, and will establish an important new direction in the field of valve cell biology. The resulting data will complement the work of other investigators examining oxygen consumption of VICs and valve leaflets, and will guide scientists and engineers developing tissue engineered valves. This work will also promote new avenues for valve disease research, since the valve cell responses (enabled by metabolism) likely contribute to disease progression, whether the initial cause was cardiac dilatation, infection, or a congenital malformation. Information about fatty acid metabolism would be relevant to the early stages of calcific aortic valve disease, since there is a growing incidence of this condition in the setting of obesity, diabetes, and metabolic syndrome. PUBLIC HEALTH RELEVANCE: Public Health Relevance Principal Investigator: Kathryn Jane Grande-Allen, Ph.D. Heart valve disease leads to hospitalization for almost 100,000 Americans every year, but the causes of heart valve disease are a mystery, especially because much of the behavior of heart valve cells has never been previously studied. This research will study the metabolism of heart valve cells, meaning how they use sugars, fatty acids, and lactate to create fuel for their activities such as migrating and making new proteins. This research will also examine how several conditions that are used to create tissue engineered heart valves affect this metabolism. This research is also relevant due to the growing incidence of aortic valve disease in the setting of obesity, diabetes, and metabolic syndrome.

描述（由申请人提供）：项目摘要首席研究员：Kathryn Jane Grande-Allen博士心脏瓣膜疾病每年为近100,000名美国人的住院授权。尽管瓣膜疾病的某些初始原因是众所周知的，但中间细胞介导的疾病机制在很大程度上尚不清楚。大多数瓣膜疾病的唯一有效治疗方法是手术修复或置换。没有用于预防或改善瓣膜疾病的医学或治疗治疗方法。剖析潜在疾病机制并开发新的医疗疗法的动力使瓣膜生物学的研究令人振奋。该领域仍处于起步阶段，但仍见证了许多有关收缩，合成，细胞通信，粘附和信号传导特征（VIC）（VIC）的发现，尤其是在与阀的组织和开发有关的情况下钙化主动脉瓣疾病。尽管如此，对瓣膜细胞的代谢有很少的研究。尽管最近的出版物已经解决了氧扩散和灌注如何影响瓣膜细胞和组织工程瓣膜，但瓣膜细胞代谢的主题在很大程度上仍未得到解决。正常成年瓣膜内的细胞保持静止（即使在这种机械活性组织中），但显示出激活并改变其表型/行为的能力，以应对各种损伤或疾病状况。这种激活过程的特征很差，导致了有关VIC的基本代谢率的几个问题，这些静态和激活条件下的基本代谢率。该代谢率也未知如何受细胞环境的影响，这意味着其周围基质和机械或化学刺激的水平。考虑到外源刺激在组织工程瓣膜的发展以及这些因素在瓣膜重塑和疾病进展中的作用，这些问题非常重要。实际上，代谢被认为是大多数细胞类型的环境压力的第一响应者。为了解决这些问题，本研究建议确定VIC的基本代谢率（AIM 1）。以下2个目标将检查细胞因子和缺氧刺激（AIM 2）和机械拉伸（AIM 3）对VICS代谢率和代谢基因表达的影响。这项研究之所以重要，是因为它将提供有关基础和压力培养条件下VIC代谢率的新的基本信息，并将在瓣膜细胞生物学领域建立重要的新方向。最终的数据将补充其他研究人员检查vics和瓣膜传单的消耗的工作，并将指导科学家和工程师开发组织工程阀。这项工作还将促进瓣膜疾病研究的新途径，因为瓣膜细胞反应（由代谢启用）可能有助于疾病进展，无论是最初的原因是心脏扩张，感染还是先天性畸形。有关脂肪酸代谢的信息将与钙化主动脉瓣疾病的早期阶段有关，因为在肥胖，糖尿病和代谢综合征的情况下，这种情况的发生率越来越大。公共卫生相关性：公共卫生相关首席研究员：凯瑟琳·简·格兰德·艾伦（Kathryn Jane Grande-Allen）博士心脏瓣膜疾病每年导致近100,000名美国人的住院治疗，但心脏瓣膜疾病的原因是一个谜，尤其是因为以前从未研究过心脏瓣膜细胞的许多行为。这项研究将研究心脏瓣膜细胞的代谢，这意味着它们如何使用糖，脂肪酸和乳酸来为其活动（例如迁移和生产新蛋白质）创造燃料。这项研究还将研究用于创建组织工程心脏瓣膜的几种条件如何影响这种新陈代谢。由于主动脉瓣疾病在肥胖，糖尿病和代谢综合征的情况下的发生率不断增长，因此这项研究也很重要。