Engineering ErbB receptor biasing for regenerating infarcted myocardium

工程ErbB受体偏向再生梗塞心肌

• 批准号: 8298966
• 负责人: SAMUEL SENYO
• 金额: $ 5.57万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298966
• 关键词: Address; Adult; Affect; Affinity; Animal Technicians; Automobile Driving; Binding; Biomedical Engineering; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cell Cycle; Cells; Clinical; Complement; Cytokinesis; Data; Development; Dimerization; EGF gene; Effectiveness; Endotoxins; Engineering; Epidermal Growth Factor; ErbB4 gene; Event; Family member; Fellowship; Fibroblast Growth Factor 1; Funding; Generations; Genetic; Goals; Growth Factor; Heart; Heart failure; Heterodimerization; Homodimerization; In Vitro; Infarction; Injury; Intervention; Investigation; Laboratories; Lead; Life; Ligands; Maps; Measurement; Methods; Microsurgery; Modeling; Molecular; Molecular Biology; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neuregulins; Organ; Outcome; Preparation; Prevention; Proliferating; Protein Biochemistry; Proteins; Quality of life; Receptor Signaling; Regenerative Medicine; Research; Research Personnel; Rodent Model; Signal Transduction; Source; Stem cells; Surgeon; Surgical Models; Technology; Testing; Therapeutic; Therapeutic Effect; Therapeutic Uses; Time; Tissues; Training; Translating; Work; attack victim; career; clinically relevant; design; dimer; effective therapy; experience; improved; in vivo; in vivo Model; injury and repair; insight; loss of function; mortality; mouse model; novel; novel therapeutics; nuclear division; periostin; prenatal; prevent; programs; receptor; repaired; research study; therapeutic development

DESCRIPTION (provided by applicant): Heart failure is a leading cause of mortality worldwide, and effective therapies to repair damaged cardiac tissue are badly needed given that myocardial regeneration is clearly inadequate in the setting of extensive injury. A critical intervention in the loss of function could be to repopulate cardiomyocytes lost as a result of the ischemic injury. The development of therapeutic strategies to stimulate endogenous cardiomyocyte proliferation could treat and/or prevent heart failure. Recent data suggest that the EGF family member neuregulin-12 (NRG) can improve survival and cardiac function in models of in vivo ischemic cardiomyopathy potentially by cardiomyocyte division. However, because the mechanism by which NRG improves cardiomyopathy outcomes is not fully understood, the full therapeutic potential of NRG remains unrealized. NRG binds its receptor ErbB4 with high affinity in the heart and induces predominantly ErbB2/ErbB4 heterodimerization, as well as ErbB4 homodimerization, leading to distinct signaling outcomes. My preliminary data suggest that biasing ErbB receptor signaling leads to different signaling in cardiomyocytes. Therefore the objective of this proposal is to utilize molecular design, protein biochemistry and in vivo molecular biology to engineer NRG ligands that bias receptor dimerization and determine their signaling outcome in the myocardium. This objective will be accomplished through two primary aims. In Aim 1, I will determine whether biasing ErbB receptor dimerization with engineered NRG ligands induces adult cardiomyocyte proliferation. In vitro findings will be confirmed with in vivo mouse models that incorporate inducible cardiac-specific deletion of ErbB receptors to establish molecular mechanisms at the receptor level, and genetic fate-mapping approaches will be used to determine if biasing ErbB signaling affects established cardiomyocytes or progenitor cells. In Aim 2, modified NRG ligands will be tested for their ability to repair the myocardium following infarction injury in vivo; this experiment will directly address a crucial clinically-relevant hypothesis. Collectively, these studies will contribute to understanding NRG-induced ErbB receptor dimerization and its effects on cardiomyopathy outcomes. In addition to fundamental mechanistic insight into ErbB signaling in the heart, these experiments have the potential to reveal a novel therapeutic strategy for cardiac regeneration. This project will also provide the crucial training in molecular biology and in vivo experimentation that I need to complement my undergraduate and graduate work in engineering, so that I can pursue a career in investigation that will translate bioengineering approaches into in vivo benefits. These advances would enable the optimization of NRG ligands to potentiate their effectiveness for repair of myocardial infarction injuries.

描述（由申请人提供）：心力衰竭是世界范围内死亡的主要原因，由于心肌再生明显不足，迫切需要有效的治疗方法来修复受损的心脏组织。功能丧失的关键干预措施可能是重新填充由于缺血性损伤而丢失的心肌细胞。刺激内源性心肌细胞增殖的治疗策略的发展可以治疗和/或预防心力衰竭。最近的数据表明，EGF家族成员神经调节蛋白-12 （NRG）可能通过心肌细胞分裂改善体内缺血性心肌病模型的生存和心功能。然而，由于NRG改善心肌病预后的机制尚不完全清楚，因此NRG的全部治疗潜力仍未实现。NRG在心脏中以高亲和力结合其受体ErbB4，主要诱导ErbB2/ErbB4异源二聚化，以及ErbB4同源二聚化，导致不同的信号转导结果。我的初步数据表明，偏倚的ErbB受体信号导致心肌细胞中不同的信号传导。因此，本研究的目的是利用分子设计、蛋白质生物化学和体内分子生物学来设计偏向受体二聚化的NRG配体，并确定其在心肌中的信号转导结果。这一目标将通过两个主要目标来实现。在目的1中，我将确定是否偏置ErbB受体二聚化与工程NRG配体诱导成人心肌细胞增殖。体外研究结果将在体内小鼠模型中得到证实，该模型包含可诱导的心脏特异性ErbB受体缺失，以在受体水平上建立分子机制，遗传命运定位方法将用于确定偏置ErbB信号是否影响已建立的心肌细胞或祖细胞。在Aim 2中，我们将测试修饰的NRG配体在体内修复梗死后心肌损伤的能力；这个实验将直接解决一个关键的临床相关假设。总的来说，这些研究将有助于理解nrg诱导的ErbB受体二聚化及其对心肌病预后的影响。除了了解心脏中ErbB信号传导的基本机制外，这些实验有可能揭示心脏再生的新治疗策略。这个项目还将提供分子生物学和体内实验方面的重要训练，这是我需要补充我的本科和研究生工程工作的，这样我就可以从事研究工作，将生物工程方法转化为体内效益。这些进展将使NRG配体的优化，以增强其修复心肌梗死损伤的有效性。