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

基本信息

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
项目类别：
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

项目摘要

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) 仍然是发病和死亡的主要原因，并且是 HF 的一种形式正在增加到接近流行病的程度，这是由持续的压力超负荷引起的（LVPO）。 LVPO 总是与细胞外基质 (ECM) 重塑增加相关，导致心肌僵硬度增加、舒张功能受损以及心力衰竭的体征和症状。一统一的观察结果是，随着 LVPO 和进展为 HF，相对平衡发生了变化基质金属蛋白酶 (MMP) 和 MMP 组织抑制剂 (TIMP) 之间发生相互作用。更多的具体来说，现在人们认识到 TIMP 表达存在很大的多样性，功能。 TIMP-4 已被证明可以改变成纤维细胞增殖、存活和胶原蛋白表达，我们现在发现，与 TIMP-1 相比，心肌水平增加 TIMP-4 实际上可以预防异常 ECM 重塑和 LVPO 功能障碍。这个项目将检验中心假设，即 LVPO 的 HF 进展是由于 TIMP-4 不足所致诱导，从而导致 TIMP 化学计量平衡发生有利于成纤维细胞的变化转化、ECM积累、心肌僵硬度增加，从而驱动心力衰竭过程向前。该项目有 3 个目标。具体目标 1 将确定向 HF 的过渡 LVPO 可以通过 TIMP-1/TIMP-4 平衡的变化来预测，这代表了一个临界点由此发生成纤维细胞转化和增殖的转变，并伴随着增加转化生长因子 (TGF) 信号传导和 ECM 积累，导致局部心肌僵硬。具体目标 2 将证明在 LVPO 的渐进模型中在猪中，通过新型水凝胶递送重组 TIMP-4 (rTIMP-4) 的区域增强系统将防止成纤维细胞转化、ECM 积累和心肌僵硬。而且，我们将证明，随着 LVPO 的发展，rTIMP-4 的本地化释放将逆转这种 ECM 表型从而降低心肌僵硬度。在具体目标 3 中，我们将推进我们的将 rTIMP-4 递送至冠状动脉内途径，并证明了进展的中断高频与 LVPO。通过一套综合的转化研究，该项目的成果将定义了关于 TIMP（例如 TIMP-4）如何促进 HF 继发性发展的新见解向 LVPO 提供一种易于转化的新诊断方法，可用于预测心力衰竭过程的进展，并最终为此建立新的治疗方向心力衰竭的重要原因。