Small molecule targeting of MLK3 for heart failure

MLK3 小分子靶向治疗心力衰竭

基本信息

批准号：
9053110
负责人：
Burns C Blaxall
金额：
$ 39万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-14 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053110
关键词：
Ablation Address Apoptosis Arrhythmia Attenuated Biological Assay Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular Pathology Cell Communication Cells Characteristics Cicatrix Communication Complement Data Disease Environment Enzymes Extracellular Matrix FDA approved Family Fibroblasts Fibrosis Functional disorder Genetic HIV Heart Heart Hypertrophy Heart failure Human Hypertrophy In Vitro Inflammation Inflammation Mediators Injury Ischemia Knock-in Mouse Knockout Mice Lead MAP Kinase Kinase Kinase MAPK14 gene MAPK8 gene Mechanics Mediating Mediator of activation protein Modeling Molecular Mus Muscle Cells Myocardial Myofibroblast Nerve Degeneration Neurons Pathologic Pathology Phenotype Phosphotransferases Play Reagent Reperfusion Therapy Rodent Role Series Specificity Stress Supporting Cell Surgical Models Testing Therapeutic Tissues Treatment Efficacy United States Validation Ventricular base cell injury cell type clinically relevant coronary fibrosis extracellular gain of function in vivo interstitial mixed lineage kinase 3 mortality mouse model new therapeutic target novel novel strategies outcome forecast parity periostin predict clinical outcome public health relevance small molecule sudden cardiac death targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Heart failure (HF), the final manifestation of most cardiovascular pathologies, is a devastating disease with poor prognosis. Pathologic cardiac remodeling (hypertrophy, fibrosis) is a known predictor of clinical outcome. We and others have demonstrated that pathologic activation of the cardiac fibroblast (CF) ("support cell") after cardiac injury releases various pro-hypertrophic/inflammatory mediators that target both cardiomyocytes (CM) ("functional cell") and fibroblasts to exacerbate remodeling. Elucidating mechanisms of this pathologic communication may hold therapeutic promise. Mixed Lineage Kinases (MLKs) are a family of stress-activated dual-specificity MAPKKKs upstream of JNK and p38 MAPKs. MLK3 in particular has been directly implicated in HIV-associated neurodegeneration (HAND), where it mediates microglial ("support cell") activation neuronal ("functional cell") damage. The similar pathogenic mechanisms of HAND and HF, namely deleterious "support cell-functional cell" communication, suggest a similar pathologic role for MLK3 in HF. However, the functional role(s) of MLKs in the heart remain largely unknown. We have generated global MLK3-/- and CF-targeted conditional MLK3fl/fl mice, in which we have found no basal cardiac phenotype; however, they are protected following myocardial injury. We have synthesized MLK3-specific inhibitory compounds, including URMC-099 (CNS-penetrant) and URMC-128 (CNS-impenetrant). URMC-099 reduced pathologic CF activation in vitro; it significantly attenuated cardiac hypertrophy and reduced interstitial fibrosis in pharmacologic and surgical models of HF, with no additive benefit in MLK3 global or conditional null mice. Our hypothesis is that MLK3 plays an important role in pathologic CF activation and HF progression and that its inhibition holds therapeutic promise for HF. To address our hypothesis, we propose the following Aims: Aim 1: Determine the therapeutic efficacy and specificity of MLK3 inhibition or ablation in clinically-relevant HF models in wild type, MLK3-/- and inducible CM or CF MLK3-/- mice. This aim will investigate the therapeutic efficacy and specificity of MLK3 pharmacologic inhibition (using our structurally distinct CNS-penetrant or -impenetrant compounds) and/or ablation (global, inducible CM, inducible resident or activated CF-restricted null mice) in ischemia-reperfusion (I/R) HF. Aim 2: Elucidate the cellular mechanisms underlying MLK3 inhibition and provide validation of MLK3 as a therapeutic target in both mouse and human HF. This aim will test the hypothesis that MLK3 inhibition or ablation will attenuate pathologic CF activation and subsequent CF/MF-CM pathologic crosstalk, using primary rodent CF and CM (Aim 1) subjected to pathogenic insults. Importantly, similar assays will ensue in human HF cardiac cells. MLK3 gain of function studies in vitro and in vivo will complement these studies. Our results may elucidate a new approach for treating HF and a novel paradigm of pathologic "support cell-functional cell" cross talk in the pathophysiology of multiple disease states.

描述（由申请人提供）：心力衰竭（HF）是大多数心血管疾病的最终表现，是一种预后不良的破坏性疾病，病理性心脏重塑（肥大、纤维化）是临床结果的已知预测因素。心脏损伤后心脏成纤维细胞（CF）（“支持细胞”）的病理激活释放出各种针对心肌细胞（CM）（“功能细胞”）的促肥大/炎症介质阐明这种病理通讯的机制可能具有治疗前景，混合谱系激酶 (MLK) 是 JNK 上游的应激激活双特异性 MAPKKK 家族，特别是与 HIV 直接相关。相关的神经变性（HAND），它介导小胶质细胞（“支持细胞”）激活神经元（“功能细胞”）损伤相似的致病机制。 HAND 和 HF，即有害的“支持细胞-功能细胞”通讯，表明 MLK3 在 HF 中具有类似的病理作用。然而，MLK 在心脏中的功能作用仍然很大程度上未知。 - 以及 CF 靶向条件 MLK3fl/fl 小鼠，我们在其中没有发现基础心脏表型；然而，我们合成了 MLK3 特异性抑制化合物，包括URMC-099（CNS 渗透剂）和 URMC-128（CNS 渗透剂）在体外可减少病理性 CF 激活；在 HF 的药物和手术模型中，它显着减轻心脏肥大并减少间质纤维化，但在治疗中没有额外的益处。 MLK3 全局或条件缺失小鼠我们的假设是 MLK3 在病理性 CF 激活和 HF 进展及其抑制中发挥重要作用。为了实现我们的假设，我们提出以下目标：目标 1：确定 MLK3 抑制或消融在野生型、MLK3-/- 和诱导型 CM 或 CF 临床相关 HF 模型中的治疗效果和特异性。 MLK3-/- 小鼠这一目标将研究 MLK3 药理抑制的治疗功效和特异性（使用我们结构独特的 CNS 渗透性或非渗透性化合物）。目标 2：阐明 MLK3 抑制的细胞机制，并验证 MLK3 作为治疗靶点。在小鼠和人类 HF 中，该目标将检验 MLK3 抑制或消融将减弱病理性 CF 激活和随后的 CF/MF-CM 病理性的假设。重要的是，在人类 HF 心脏细胞中进行类似的体外和体内功能获得研究将补充我们的结果。治疗心力衰竭的方法以及多种疾病状态病理生理学中病理性“支持细胞-功能细胞”串扰的新范例。