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Engineering ErbB receptor biasing for regenerating infarcted myocardium

工程ErbB受体偏向再生梗塞心肌

基本信息

批准号：
8124272
负责人：
SAMUEL SENYO
金额：
$ 5.3万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/8124272
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: NRG stimulates cardiomyocyte proliferation, but its potential clinical use is limited by an incomplete understanding of its mechanism of action and a lack of therapeutic potency. We propose a strategy to develop an improved mechanistic understanding of NRG-stimulated cardiomyocyte proliferation. These advances would enable the optimization of NRG ligands to maximize their effectiveness for repair of injury due to myocardial infarction.

描述(申请人提供)：心力衰竭是世界范围内死亡的主要原因，鉴于心肌再生在大面积损伤的情况下明显不足，迫切需要有效的治疗来修复受损的心脏组织。对功能丧失的一个关键干预措施可能是重新填充因缺血损伤而丢失的心肌细胞。开发刺激内源性心肌细胞增殖的治疗策略可以治疗和/或预防心力衰竭。最近的数据表明，EGF家族成员NeuRegin-12(NRG)可能通过促进心肌细胞分裂来改善在体缺血性心肌病模型的存活率和心功能。然而，由于NRG改善心肌病预后的机制尚不完全清楚，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异二聚化和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，偏向ErbB受体信号导致心肌细胞中不同的信号。因此，这项建议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，并确定它们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。在目标1中，我将确定用工程NRG配体偏置ErbB受体二聚体是否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，该模型包括可诱导的心脏特异性ErbB受体缺失，以在受体水平建立分子机制，并将使用遗传命运映射方法来确定偏置ErbB信号是否影响已建立的心肌细胞或祖细胞。在目标2中，将测试修饰的NRG配体在体内修复心肌梗死损伤后的能力；本实验将直接解决一个关键的临床相关假说。总之，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。除了对ErbB信号在心脏中的基本机制的洞察外，这些实验还有可能揭示一种新的心脏再生治疗策略。这个项目还将提供关键的分子生物学和活体实验方面的培训，这是我在工程学本科和研究生工作中所需要的，这样我就可以从事将生物工程方法转化为体内益处的研究工作。这些进展将使优化NRG配体以增强其修复心肌梗死损伤的有效性。公共卫生相关性：NRG刺激心肌细胞增殖，但由于对其作用机制的不完全了解和治疗效力的缺乏，其潜在的临床应用受到限制。我们提出了一种策略，以提高对NRG刺激的心肌细胞增殖的机制的理解。这些进展将使NRG配体的最优化能够最大限度地发挥其修复心肌梗死损伤的有效性。