Small molecule targeting of MLK3 for heart failure

MLK3 小分子靶向治疗心力衰竭

• 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
• 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

 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，是一种预后很差的毁灭性疾病。病理性心脏重构(肥大、纤维化)是临床预后的已知预测指标。我们和其他人已经证明，心脏损伤后心脏成纤维细胞(CF)(“支持细胞”)的病理激活会释放各种促肥大/炎症介质，这些介质既针对心肌细胞(CM)(“功能细胞”)，也针对成纤维细胞，以加剧重构。阐明这种病理沟通的机制可能具有治疗前景。混合型MAPKs是JNK和p38MAPKs上游的应激激活的双特异性MAPKKs家族。尤其是MLK3直接参与了HIV相关的神经退行性变(HAND)，它介导了小胶质细胞(“支持细胞”)激活神经元(“功能细胞”)的损伤。Hand和HF相似的致病机制，即有害的“支持细胞-功能细胞”通讯，提示MLK3在HF中具有相似的病理作用。然而，MLK在心脏中的功能作用(S)在很大程度上仍不清楚。我们已经产生了全球MLK3-/-和CF靶向条件MLK3fl/fl小鼠，在这些小鼠中，我们没有发现基本的心脏表型；然而，它们在心肌损伤后受到保护。我们已经合成了MLK3特异性抑制化合物，包括URMC-099(中枢神经系统渗透剂)和URMC-128(中枢神经系统渗透剂)。URMC-099在体外减少病理性的CF激活；在药理学和外科模型的HF中，它显著减轻心肌肥厚和减少间质纤维化，在MLK3全局或条件性空白小鼠中没有额外的益处。我们的假设是，MLK3在病理性CF激活和HF进展中发挥重要作用，其抑制具有治疗HF的前景。为了解决我们的假设，我们提出了以下目标：目的1：在野生型、MLK3-/-和诱导型CM或CFMLK3-/-小鼠中，确定MLK3抑制或消融对临床相关心力衰竭模型的治疗效果和特异性。这一目的将研究MLK3药物抑制(使用我们结构上不同的CNS穿透性或非渗透性化合物)和/或消融(全局的、可诱导的CM、可诱导的驻留或激活的Cf限制的零小鼠)在缺血再灌注(I/R)HF中的疗效和特异性。目的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心衰中的作用。这一目标将在原始啮齿动物CF和CM(Aim 1)受到病原性侮辱的情况下，检验MLK3抑制或消融将减弱病理性CF激活和随后的CF/MF-CM病理串扰的假说。重要的是，类似的检测也将在人的HF心肌细胞中进行。MLK3在体外和体内的功能研究将补充这些研究。我们的结果可能阐明一种治疗心力衰竭的新方法，以及在多种疾病状态的病理生理学中的一种新的病理“支持细胞-功能细胞”串扰模式。