Young, Lindon H

年轻的林登 H

• 批准号: 10324843
• 负责人: Lindon H Young
• 金额: $ 56.03万
• 依托单位: YOUNG THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-10 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324843
• 关键词: Acute; Animals; Applications Grants; Area; Awareness; Blood; Blood flow; Blood specimen; Cardiac; Cell Death; Cell membrane; Cells; Chlorides; Chronic Phase; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Coronary artery; Creatine Kinase; Cytokine Activation; Data; Dyes; EFRAC; Echocardiography; Failure; Family suidae; Free Radical Scavenging; Freezing; Funding; Future; Generations; Goals; Heart; Heart Injuries; Heart failure; Hindlimb; Hour; Human; Hydrogen Peroxide; Immunohistochemistry; Incidence; Infarction; Intervention; Interview; Investigational Drugs; Ischemia; Isoenzymes; Lead; Left; Legal patent; Leukocytes; Life; Measures; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial tissue; Myristic Acids; NADPH Oxidase; NOS3 gene; Organ; Outcome; Oxygen; PKC-betaII; Pathway interactions; Patients; Peptides; Permeability; Pharmacological Treatment; Pharmacology; Phase; Philadelphia; Phorbol Esters; Preventive treatment; Proteins; Protocols documentation; Rattus; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Risk; Small Business Innovation Research Grant; Solubility; Source; Stains; Superoxides; Surgeon; Testing; Therapeutic; Time; Tissues; Trans-Activators; Transcription Coactivator; Transplant Recipients; Troponin I; XDH gene; Xanthine Oxidase; animal efficacy; attenuation; base; cardioprotection; cell injury; clinical candidate; computerized; cysteinylcysteine; cytokine; efficacy study; experience; experimental study; free radical oxygen; heart damage; heart function; heart preservation; improved; in vivo; in vivo Model; indexing; inhibitor/antagonist; insight; male; mortality; novel; porcine model; preservation; prevent; protective effect; protein kinase C epsilon; restoration; therapeutically effective

PROJECT SUMMARY We are seeking funding to test the cardio protective effects of a novel new protein kinase C epsilon (PKCε) inhibitor (YT-002) and a novel protein kinase C beta II (PKCβII) inhibitor (YT-004) in the setting of porcine myocardial ischemia reperfusion (I/R) in vivo when given at the beginning of reperfusion. There currently is no approved pharmacological treatment/preventative for the I/R injury. We are fully aware of the past failures in this area. Literally all previous attempts have taken the oxygen free radical scavenging approach. We believe this underlies, at least in part, the reason there have been no successful pharmacological therapeutics for cardiac I/R injury to date. Once reactive oxygen species are generated the damage is immediate and scavenging is ineffective. Our approach – never been tried before – is to inhibit the generation of reactive oxygen species thus preventing their damage during reperfusion. Interviews we conducted with 22 interventional cardiologists overwhelmingly support the idea that such preservation of myocardial tissue and function would represent a significant long-term benefit to the patients experiencing ischemia-reperfusion injury leading to a decrease in the incidence of heart failure. Previous data from our lab with another compound YT-001 (identical mechanism of action as YT-002) demonstrated a significant inhibition of hydrogen peroxide generation in vivo, and a remarkable sparing of tissue damage and cardiac function post reperfusion in both the ex vivo rat I/R heart and the in vivo porcine myocardial I/R model. However, YT-001 has limited solubility and remaining patent life. Our new molecules (YT-002 and YT-004) have dramatically improved solubility, potency and new patent life. We have already demonstrated impressive infarct size reduction and cardiac function protection in isolated rat I/R hearts with YT-002 and YT-004. In this proposal, we will evaluate the cardio protective effects of YT-002 and YT-004 on ischemia reperfusion in the Gorman pig model (19). In addition to the animal’s vital signs, ejection fraction (measured by echocardiography) will be monitored (as an index of cardiac function/contractility) as well as cardiac proteins (e.g., troponin I) as an index of tissue damage throughout the protocol. Three hours after reperfusion, the hearts will be excised, and stained for direct assessment of cardiac damage (infarct size). Immunohistochemistry on frozen heart sections will be performed in Dr. Young’s lab at PCOM to detect PKCε and PKCβII localization. Based upon previously generated pig heart data with the PKCε inhibitor YT-001, we expect to see a dramatic in vivo preservation of cardiac tissue and function compared to animals receiving scrambled peptide control. These positive data will provide additional justification for performing longer-term animal efficacy studies and eventually Investigational New Drug (IND) enabling studies in support of human clinical trials.

项目概要 我们正在寻求资金来测试新型蛋白激酶 C epsilon (PKCε) 的心脏保护作用 抑制剂 (YT-002) 和新型蛋白激酶 C beta II (PKCβII) 抑制剂 (YT-004) 在猪中的应用 再灌注开始时给予体内心肌缺血再灌注（I/R）。目前没有 批准的 I/R 损伤药物治疗/预防。我们充分认识到过去在这方面的失败 区域。从字面上看，之前所有的尝试都采用了氧自由基清除方法。我们相信这一点 至少在一定程度上是目前尚无成功的心脏病药物治疗方法的基础 迄今为止的 I/R 损伤。一旦产生活性氧，就会立即造成损害，并且需要清除 无效。我们的方法——以前从未尝试过——是抑制活性氧的产生，从而 防止它们在再灌注过程中受损。我们对 22 名介入心脏病专家进行了采访 绝大多数人支持这样的观点，即这种心肌组织和功能的保存代表了一种 对经历缺血再灌注损伤的患者具有显着的长期益处，导致 心力衰竭的发生率。我们实验室先前使用另一种化合物 YT-001 得到的数据（与 作用如 YT-002) 表现出对体内过氧化氢产生的显着抑制，并且 离体大鼠 I/R 心脏和再灌注后的组织损伤和心脏功能均显着减少 体内猪心肌 I/R 模型。然而，YT-001 的溶解度和剩余专利寿命有限。我们的 新分子（YT-002 和 YT-004）显着提高了溶解度、效力和新的专利寿命。我们 已经在离体大鼠 I/R 中表现出令人印象深刻的梗塞面积减少和心脏功能保护 心与 YT-002 和 YT-004。在本提案中，我们将评估YT-002和YT-002的心脏保护作用 YT-004 对 Gorman 猪模型缺血再灌注的影响 (19)。除了动物的生命体征外，喷射 还将监测分数（通过超声心动图测量）（作为心脏功能/收缩力的指数） 作为心脏蛋白（例如肌钙蛋白 I）作为整个协议中组织损伤的指标。三小时后 再灌注时，心脏将被切除并染色以直接评估心脏损伤（梗塞大小）。 冷冻心脏切片的免疫组织化学将在 PCOM 的 Young 博士实验室进行，以检测 PKCε 和 PKCβII 定位。根据之前使用 PKCε 抑制剂 YT-001 生成的猪心脏数据，我们 与接受治疗的动物相比，期望看到心脏组织和功能在体内得到显着的保存 乱序肽对照。这些积极的数据将为长期执行提供额外的理由 动物功效研究以及最终的研究性新药 (IND) 使研究能够支持人类 临床试验。