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DYRK1a as a therapeutic target to treat myocardial infarction

DYRK1a作为治疗心肌梗死的治疗靶点

基本信息

批准号：
10458688
负责人：
Matthew J Wolf
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10458688
关键词：
Ablation Address Adult Apoptosis Arrhythmia Blood capillaries Cardiac Myocytes Cardiovascular Diseases Cell Cycle Cells Cessation of life Clinical Complement Data Development Diphtheria Toxin Future Genetic Goals Harmine Heart Heart failure Hyperplasia Infarction Injury Investigation Ischemia Knock-out Knockout Mice Left Ventricular Function Left Ventricular Remodeling Morbidity - disease rate Mosaicism Mus Muscular Atrophy Myocardial Myocardial Infarction Myocardial Ischemia Myocardial Reperfusion Myocardium Neonatal Outcome Pathway interactions Pharmaceutical Preparations Pharmacology Phosphotransferases Regenerative capacity Reperfusion Therapy Reporter RiboTag Ribosomal Proteins Signal Pathway Signal Transduction Societies Specificity Technology Testing Transcript Transgenic Mice Tyrosine Phosphorylation Ventricular Function Work base candidate identification density design druggable target event cycle functional improvement heart function improved improved outcome inhibitor ischemic cardiomyopathy kinase inhibitor mortality novel paracrine secretory protein therapeutic target

项目摘要

ABSTRACT Although outcomes after myocardial infarctions (MIs) have improved, cardiomyocytes (CMs) are lost even with successful reperfusion. This loss contributes to adverse remodeling, ischemic cardiomyopathy, heart failure, arrhythmia, and death. Current therapies can only slow or reverse isolated aspects of ischemic heart disease, and there are no reliable therapies available to replace the cardiac muscle loss to MI. Identifying therapeutic targets and drugs to protect the myocardium after injury will be groundbreaking, address unmet clinical needs, and represent new strategies to treat cardiovascular diseases. Our goals are to identify and validate druggable targets that induce controlled CM cycling and improve heart function after injury. However, two challenges exist: (1) the identification of candidate pathways to stimulate CM cycling with the intent to improve cardiac function after injury, and (2) the accurate quantification of CM cycling events in adult myocardium. Therefore, we conducted investigations to address the two challenges. First, we identified an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1a), Harmine, increased CM cycling, and improved ventricular function after MI. Next, we generated CM-specific DYRK1a knockout mice and observed CM hyperplasia at baseline and improved LV function after MI, suggesting DYRK1a contributes to CM function. Second, we designed and validated a unique transgenic mouse (denoted αDKRC) that drives Cre in adult cycling CMs. αDKRC complements existing technologies such as Mosaic Analysis with Double Markers (MADM); however, the ability to restrict Cre expression to adult cycling CMs is an advance in the field. We used αDKRC::DTA mice to express Diphtheria toxin in adult cycling CMs and observed that the loss of endogenously cycling CMs worsened myocardial function after MI. Since cycling CMs are scarce, the findings suggest that cycling CMs may contribute to myocardial function beyond the concept of a CM as only a contractile cell, perhaps by expressing paracrine factors. This potential mechanism suggests that modest increases in cycling CMs may have a more significant impact on cardiac function after MI because cycling CMs serve functions beyond the concept of contractility. Based on preliminary data, we hypothesize that the inhibition of DYRK1a improves myocardial function after MI, in part, through enhanced CM cycling and the cycling CMs exert their effects via paracrine factors. We will test our hypothesis in the following Aims: (1) The CM-specific ablation of DYRK1a during development protects LV function after MI through enhanced cell cycling, (2) The post- developmental ablation of DYRK1a in adult CMs will improve LV function after MI, and (3) Cycling CMs contribute to LV function after MI by expressing paracrine factors. The proposed investigations will define the potential of DYRK1a inhibition as a treatment of MI, identify the mechanisms through which DYRK1a exerts its effects in CMs, and characterize novel paracrine factors expressed by cycling CMs that potentially serve as new future therapeutic targets.

摘要