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（应用程序提供）：心力衰竭（HF），大多数心血管病理的最终表现，是一种毁灭性的疾病，预后不良。病理心脏重塑（肥大，纤维化）是临床结果的已知预测指标。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”）的病理激活释放出靶向心肌细胞（CM）（CM）（“功能性细胞”）（“功能性细胞”）和成纤维细胞的各种促性性/炎症介质，以使重塑化重塑。阐明这种病理沟通的机制可能会有治疗的希望。混合谱系激酶（MLK）是JNK和P38 MAPK上游的应激激活双特异性MAPKKK的家族。特别是MLK3直接与HIV相关的神经变性（Hand）有关，其中它介导了小胶质细胞（“支持细胞”）激活神经元（“功能细胞”）损伤。手和HF的类似的致病机制，即删除的“支持细胞功能细胞”的通信，这表明MLK3在HF中具有相似的病理作用。但是，MLK在心脏中的功能作用仍然很大程度上是未知的。我们已经产生了全局MLK3 - / - 和CF靶向有条件的MLK3FL/FL小鼠，其中我们没有发现基本的心脏表型。但是，它们在心肌损伤后受到保护。我们已经合成了MLK3特异性抑制剂化合物，包括URMC-099（CNS-PENETRANT）和URMC-128（CNS- IMPENETRANT）。 URMC-099在体外降低了病理CF激活；它显着减弱了心脏肥大和HF的药物模型和手术模型中的间质纤维化降低，在MLK3全球或条件无效的NULL小鼠中没有附加益处。我们的假设是MLK3在病理CF激活和HF进展中起重要作用，并且其抑制作用是HF的热希望。为了解决我们的假设，我们提出了以下目的：目标1：确定MLK3抑制作用或在野生型HF模型中的MLK3抑制作用或消融的特异性，MLK3 - / - 以及诱导的CM或CF MLK3 - / - 小鼠。该目标将研究MLK3药物抑制的治疗效率和特异性（使用我们在缺血 - repreprusion（I///////r）中的MLK3药物抑制作用（使用我们的结构上不同的CNS-PENETRANT或-IMPENETRANT化合物）和/或消融（全球，可诱导的常驻CM，可诱导的常驻或活化的CF诱导的CF-RESIDEC NULL小鼠）。 AIM 2：阐明MLK3抑制作用的细胞机制，并提供MLK3作为小鼠和人HF的治疗靶标的验证。该目的将检验以下假设：MLK3抑制或消融将减少病理CF激活以及随后使用原发性啮齿动物CF和CM（AIM 1）受到致病性侮辱的病理CF/MF/MF-CM病理串扰。重要的是，在人HF心脏细胞中将进行类似的测定。 MLK3在体外和体内的功能研究增益将补充这些研究。我们的结果可能阐明了一种新的方法来治疗HF和一种新型的病理学“支持细胞功能细胞”的范式，以多种疾病状态的病理生理学进行交流。