Unconventional IL-1 signaling in heart failure

心力衰竭中的非常规 IL-1 信号传导

基本信息

批准号：
10560648
负责人：
Antonio Abbate
金额：
$ 0.7万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-20 至 2023-02-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10560648
关键词：
Adaptor Signaling Protein Apical Binding Cardiac Cardiac Myocytes Cardiomyopathies Clinical Research Coronary Data Development Diagnosis Disease Disease Marker Dissociation Dizziness Dose Dyspnea Elderly Epidemic Exposure to Fatigue Frequencies Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genetic Heart Heart failure Hospitalization Hour In Vitro Incidence Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 Receptors Interruption Ischemia Knockout Mice Knowledge Ligation Link Malignant Neoplasms Measures Mediating Mediator Modeling Mus Myeloid Cells Myocardial dysfunction Myocardial tissue NF-kappa B Operative Surgical Procedures Output PDE 3B PIK3CG gene Pathway interactions Patients Phosphatidylinositols Phosphotransferases Play Population Predisposition Prevalence Prognosis Property Protein Isoforms Proteins Quality of life Receptor Signaling Role Signal Transduction Small Interfering RNA Symptoms System Testing Time anakinra beta-adrenergic receptor chemokine receptor cofactor cost cytokine desensitization epidemiologic data heart function hospital readmission improved in vivo inhibitor mRNA Expression mortality mouse model novel therapeutic intervention novel therapeutics pharmacologic preclinical study preservation pressure prevent protein expression reduce symptoms scaffold systemic inflammatory response

项目摘要

Heart failure (HF) represents a final common pathway for both ischemic and non-ischemic cardiomyopathy, with an annual incidence >600,000 new cases each year, a disease prevalence >6 million patients, and an estimated annual cost >$30 billion in the USA alone. Improved understanding of HF pathophysiology throughout recent decades has led to critical advances in HF prognosis through neurohormonal blockade. Despite these improvements, the HF mortality rate remains extraordinarily high (>30% within 5 years of diagnosis) and HF remains the leading cause for hospitalization in patients >65 years (a growing segment of the US population). The HF epidemiologic data suggest that the current treatment paradigm fails to interrupt one or more key pathophysiologic mechanisms of HF, and confirm the urgent need to develop novel therapeutic approaches to alleviate symptoms of HF, improve quality of life, and reduce re-hospitalization for HF. The evidence supporting the presence of inflammation in HF is overwhelming. One of the unanswered questions is whether inflammation plays a key role in the progression of HF or is merely a marker of disease. Recent data from our group and others have shown that the systemic inflammatory response in patients with HF can be inhibited with the use of a targeted Interleukin-1 (IL-1) blockers, anakinra or canakinumab. Both in preclinical and clinical studies, in parallel with reducing systemic inflammation, IL-1 blockers preserved or restored cardiac function, whether the effects on systemic inflammation and on cardiac function are intertwined and cannot be dissociated, or whether they are independent has not been explored. IL-1 is a master regulator of the inflammatory response, namely NF-kB activation, that is shared with many other cytokines and is part of the redundancy of the system. An unconventional signaling of the IL-1 receptor signaling through the phosphoinositide-3 kinase γ (PI3Kγ) has been characterized in inflammation and cancer. Whether IL-1 signaling in HF is mediated through PI3Kγ remains unknown. We hypothesize that enhanced levels of IL-1 increase PI3K p110γ expression in cardiomyocytes, that in turn results in selective induction of p87 co- signaling, and cardiac dysfunction through a scaffolding function on PDE3B. To test this hypothesis, we will determine whether IL-1 induces p110γ and p87 in cardiomyocytes in vitro and in vivo (Aim #1); whether PI3Kγ mediates IL-1 induced systolic dysfunction in vivo (Aim #2); and whether we can distinguish the kinase- dependent from the scaffolding function of PI3Kγ in cardiac dysfunction (Aim #3). Determining the mechanisms by which inflammation, and IL-1 in specific, contributes to cardiac dysfunction may open the way to more and better ways to prevent and treat heart failure – which is an urgent unmet need.

心力衰竭 (HF) 是缺血性和非缺血性心肌病的最终共同途径，每年新发病例数超过 600,000 例，患病率超过 600 万患者，仅在美国每年估计费用就超过 300 亿美元近几十年来，人们对心力衰竭病理生理学的了解不断加深，通过神经激素阻断在心力衰竭预后方面取得了重大进展，尽管取得了这些进展，心力衰竭死亡率仍然非常高（>30%）。诊断后 5 年内），心力衰竭仍然是 65 岁以上患者（美国人口中越来越多的人）住院的主要原因。心力衰竭流行病学数据表明，当前的治疗模式无法中断心力衰竭的一种或多种关键病理生理机制。，并确认迫切需要开发新的治疗方法来减轻心力衰竭症状，改善生活质量，并减少心力衰竭的再住院率。支持心力衰竭存在炎症的证据是压倒性的。炎症是否在心力衰竭的进展中发挥关键作用，或者仅仅是疾病的标志物，我们小组和其他人的最新数据表明，使用靶向白介素-1可以抑制心力衰竭患者的全身炎症反应。 IL-1) 阻滞剂、阿那白滞素或卡那奴单抗在临床前和临床研究中，在减少全身炎症的同时，IL-1 阻滞剂可以保留或恢复心脏功能，无论对全身炎症和心脏功能的影响是否相互交织。 IL-1 是炎症反应（即 NF-kB 激活）的主要调节因子，与许多其他细胞因子共享，是系统冗余的一部分。通过磷酸肌醇 3 激酶 γ (PI3Kγ) 进行的 IL-1 受体信号传导已在炎症和癌症中得到表征，但我们仍不清楚 HF 中的 IL-1 信号传导是否是通过 PI3Kγ 介导的。确保 IL-1 水平的增加会增加心肌细胞中 PI3K p110γ 的表达，进而导致 p87 协同信号传导的选择性诱导，并通过 PDE3B 上的支架功能导致心脏功能障碍。为了检验这一假设，我们将确定 IL-1 是否存在。在体外和体内诱导心肌细胞中的 p110γ 和 p87（目标 #1）；PI3Kγ 是否介导体内 IL-1 诱导的收缩功能障碍（目标 #2）；以及我们是否能够区分心脏功能障碍中 PI3Kγ 的激酶依赖性和支架功能（目标#3），确定炎症（特别是 IL-1）导致心脏功能障碍的机制可能会为更多更好的治疗开辟道路。预防和治疗心力衰竭的方法——这是一个紧迫的未满足的需求。