Therapeutic targeting of tissue inhibitor-4 in hypertrophy and failure

组织抑制剂 4 在肥大和衰竭中的治疗靶向

• 批准号: 9174201
• 负责人: FRANCIS G SPINALE
• 金额: $ 36.17万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-22 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174201
• 关键词: Admission activity; Animal Model; Apoptosis; Attenuated; Biological Assay; Cause of Death; Collagen; Country; Data; Development; Diagnosis; Diagnostic; Disease; EFRAC; Epidemic; Equilibrium; Event; Extracellular Matrix; Failure; Family suidae; Fibroblasts; Functional disorder; Gel; Growth; Healthcare; Heart failure; Hospitals; Hydrogels; Hypertrophy; In Vitro; Individual; Injection of therapeutic agent; Interruption; Label; Left; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Medical; Methods; Modeling; Morbidity - disease rate; Muscle; Myocardial; Myocardium; Outcome; Patients; Phenotype; Physiologic intraventricular pressure; Process; Production; Public Health; Pulmonary Capillary Wedge Pressure; Recombinants; Refractory; Research; Resistance; Resources; Secondary to; Severities; Signal Transduction; Signaling Molecule; Signs and Symptoms; Symptoms; Syndrome; System; Testing; Therapeutic; Tissues; Transforming Growth Factors; blood pump; cell type; disability; inhibitor/antagonist; insight; mortality; novel; novel diagnostics; novel therapeutics; outcome forecast; pre-clinical; pressure; prevent; response; therapeutic target; tissue inhibitor of metalloproteinase 4; transdifferentiation; translational study; treatment strategy

Heart failure (HF) continues to be a leading cause of morbidity and mortality, and one form of HF that is increasing to near epidemic proportions is that which arises from a sustained pressure overload (LVPO). LVPO is invariably associated with increased extracellular matrix (ECM) remodeling, causing increased myocardial stiffness, impaired diastolic function, and the signs and symptoms of HF. One unifying observation is that with LVPO and the progression to HF, a shift in the relative balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) occur. More specifically, it is now recognized that a large diversity exists with respect to TIMP expression and function. TIMP-4 has been shown to alter fibroblast proliferation, survival, and collagen expression, and we have now identified that in contrast to that of TIMP-1, increased myocardial levels of TIMP-4 may actually prevent abnormal ECM remodeling and dysfunction with LVPO. This project will test the central hypothesis that HF progression with LVPO is due to inadequate TIMP-4 induction, thereby causing a shift in the TIMP stoichiometric balance favoring fibroblast transformation, ECM accumulation, increased myocardial stiffness, and thus drives the HF process forward. There are 3 aims of this project. Specific Aim 1 will establish that a transition to HF with LVPO can be predicted by a shift in TIMP-1/TIMP-4 balance and that this represents a tipping point whereby a shift in fibroblast transformation and proliferation occurs, accompanied by increased transforming growth factor (TGF) signaling and ECM accumulation, causing a rapid rise in regional myocardial stiffness. Specific Aim 2 will demonstrate that in a progressive model of LVPO in pigs, regional augmentation of recombinant TIMP-4 (rTIMP-4) through a novel hydrogel delivery system will prevent fibroblast transformation, ECM accumulation, and myocardial stiffness. Moreover, we will demonstrate that localized release of rTIMP-4 following the development of LVPO will reverse this ECM phenotype and thereby reduce myocardial stiffness. In Specific Aim 3, we will advance our delivery of rTIMP-4 to an intracoronary approach and demonstrate an interruption in the progression to HF with LVPO. Through an integrated set of translational studies, the outcomes from this project will define a new insight into how TIMPs, such as TIMP-4, contribute to the development of HF secondary to LVPO, provide a readily translatable approach in terms of a new diagnostic that can be used to predict the progression of this HF process, and finally establish a novel therapeutic direction for this significant cause of HF.

心力衰竭（HF）仍然是发病率和死亡率的主要原因，而一种形式的HF形式 越来越多的流行比例是由持续压力超负荷产生的 （LVPO）。 LVPO总是与细胞外基质（ECM）重塑相关，导致 心肌刚度增加，舒张功能受损以及HF的体征和症状。一 统一的观察结果是，随着LVPO和向HF的发展，相对平衡的转变 在MMP的基质金属蛋白酶（MMP）和组织抑制剂（TIMP）之间发生。更多的 具体而言，现在已经认识到，关于TIMP表达和 功能。 TIMP-4已显示会改变成纤维细胞增殖，生存和胶原蛋白 表达，我们现在已经确定，与TIMP-1相比，心肌水平增加 TIMP-4的of实际上可以防止ECM重塑异常与LVPO功能障碍。这个项目 将测试中心假设，即LVPO的HF进展是由于TIMP-4不足所致 诱导，从而导致TIMP化学计量平衡有利于成纤维细胞 转化，ECM积累，增加心肌刚度，从而驱动HF过程 向前。该项目有3个目标。具体目标1将确定与HF的过渡 LVPO可以通过TIMP-1/TIMP-4余额的变化来预测，这代表了一个临界点 从而发生成纤维细胞转化和增殖的转移，伴随着增加 转化生长因子（TGF）信号传导和ECM积累，导致迅速上升 区域心肌僵硬。特定目标2将证明在LVPO的渐进模型中 在猪中，重组TIMP-4（RTIMP-4）通过新型水凝胶递送的区域增强 系统将防止成纤维细胞转化，ECM积累和心肌刚度。而且， 我们将证明LVPO开发后RTIMP-4的局部发布将逆转 这种ECM表型，从而降低心肌刚度。在特定目标3中，我们将提高我们的 将RTIMP-4传递到冠状动脉内方法，并证明了进展的中断 HF带LVPO。通过一组集成的翻译研究，该项目的结果将 定义有关TIMP-4等TIMP的新见解，有助于HF次要的发展 到LVPO，提供一种可轻松翻译的方法，以一种可用于的新诊断方法 预测此HF过程的进展，并最终为此建立一个新的治疗方向 HF的重要原因。