Novel Medicinal Chemicals: Cardiomyogenesis from Human Stem Cells

新型药用化学品：人类干细胞的心肌发生

• 批准号: 8058646
• 负责人: John R Cashman
• 金额: $ 17.25万
• 依托单位: CHEMREGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058646
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Address; Age; Age-Years; American; American Heart Association; Area; Biological Assay; Biology; Biotechnology; Cardiac; Cardiac Myocytes; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cellular Assay; Chemicals; Colony-Forming Units Assay; Data; Defibrillators; Development; Devices; Differentiation Inducer; Direct Costs; Disease; Drug Interactions; Facilities and Administrative Costs; Failure; Goals; Heart; Heart Diseases; Heart Injuries; Heart Transplantation; Heart failure; Heart-Assist Devices; Hospitalization; Housing; Human; Immunosuppressive Agents; Implant; In Vitro; Incidence; Individual; Industry; Lead; Libraries; Maps; Modification; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardium; Natural regeneration; Pacemakers; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Population; Preparation; Process; Production; Pump; Reagent; Regenerative Medicine; Research; Societies; Source; Staging; Stem Cell Research; Stem cells; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Human Experimentation; Tissues; Transplant Recipients; Transplantation; United States; Western World; Work; analog; attack victim; base; cardiogenesis; commercialization; cost; economic cost; embryonic stem cell; heart function; human embryonic stem cell; human stem cells; implantation; improved; induced pluripotent stem cell; injured; member; novel; productivity loss; research study; safety testing; small molecule; stem; stem cell differentiation; stem cell therapy; tool

DESCRIPTION (provided by applicant): Over 1-2% of Americans greater than 65 years of age have heart disease. According to the American Heart Association, heart failure is one of the most common causes of hospitalization for patients over 65 years of age in the Western world and as the population ages, this situation will only get worse. Currently, more than 5 million Americans suffer from heart failure. In 2009, the economic cost (direct and indirect) to US society for heart disease was in excess of $37 billion per year. Certain diseases related to heart muscle failure or heart muscle weakening are treatable with drugs or devices such as defibrillators, pacemakers or implanted pumps. However, in heart attacks, when heart muscle cells die, transplantation becomes the only option because cardiomyocyte regeneration in the human heart is generally very limited. Today, unfortunately, there is considerably less heart transplantation tissue available than the current need for transplants. Tens of thousands of hearts could be used each year for transplants but only about 2,000 hearts are available. Chemical biology approaches to embryonic stem cell (ESC) research offers considerable promise for rectifying this problem. However, despite progress, increasing the efficiency of stem or progenitor cells to become human cardiomyocytes has been very challenging. The main problem with increasing the yield of cardiomyocytes is the lack of effective ways to induce ESCs to afford cardiomyocytes involved in cardiogenesis. A critical issue is the low yields of cardiomyocytes from in vitro differentiation processes. An economically viable biotechnological process using readily available and inexpensive differentiation agents is needed. Herein, we propose to use a powerful combination of high content and high throughput cellular assays and dynamic medicinal chemistry to develop pure, easy to make, small molecule "toolbox" compounds to promote the induction of hESCs that will differentiate into cardiomyocytes. A promising new cardiomyocyte differentiation agent (i.e., compound 1) has been identified and refinement and development of this agent is the focus of this proposal. The Specific Aims include: 1) Test compounds structurally related to 1 as inducers of cardiomyocytes in a validated mouse ESC assay and 2) Test potent compounds identified in Aim 1 in a validated human ESC assay for cardiomyocyte differentiation. Based on our encouraging Preliminary Results successful completion of the proposed work will provide an inexpensive toolbox of reagents useful for the induction of cardiomyocytes from human ESCs of utility in a biotechnological sense. Preparation of human cardiomyocytes in this manner will provide large numbers of cardiomyocytes and will be of widespread use to the CRO, biotechnology or Big Pharma industry to help individuals that suffer from heart failure including myocardial infarct as well as to do drug safety tests with human cardiomyocytes to decrease adverse drug-drug interactions and develop safer drugs. PUBLIC HEALTH RELEVANCE: For heart attack victims, stem cell therapy may provide a way to regenerate damaged heart muscle cells. Current therapies are only able to improve heart function. The goal of our work is to use chemical biology to develop small molecule "toolbox" compounds that will stimulate stem cell differentiation and produce cardiomyocytes. Ultimately, the results from this work will provide reagents for use to grow cardiomyocytes for use in a biotechnology process to treat heart disease.

描述（由申请人提供）：65 岁以上的美国人中有超过 1-2% 患有心脏病。据美国心脏协会称，心力衰竭是西方世界65岁以上患者住院的最常见原因之一，随着人口老龄化，这种情况只会变得更糟。目前，超过 500 万美国人患有心力衰竭。 2009年，美国社会因心脏病造成的经济损失（直接和间接）每年超过370亿美元。某些与心肌衰竭或心肌衰弱相关的疾病可以通过药物或设备治疗，例如除颤器、起搏器或植入泵。然而，在心脏病发作时，当心肌细胞死亡时，移植成为唯一的选择，因为人心脏中的心肌细胞再生通常非常有限。不幸的是，如今可用的心脏移植组织远远少于目前的移植需求。每年有数万颗心脏可用于移植，但可用的心脏仅有约 2000 颗。胚胎干细胞（ESC）研究的化学生物学方法为解决这一问题提供了广阔的前景。然而，尽管取得了进展，提高干细胞或祖细胞变成人类心肌细胞的效率仍然非常具有挑战性。增加心肌细胞产量的主要问题是缺乏有效的方法来诱导ESCs提供参与心脏发生的心肌细胞。一个关键问题是体外分化过程中心肌细胞的产量低。需要一种经济可行的生物技术方法，使用容易获得且廉价的分化剂。在此，我们建议使用高含量和高通量细胞测定和动态药物化学的强大组合来开发纯的、易于制造的小分子“工具箱”化合物，以促进 hESC 分化为心肌细胞的诱导。一种有前途的新型心肌细胞分化剂（即化合物 1）已经被发现，该剂的完善和开发是本提案的重点。具体目标包括：1) 在经过验证的小鼠 ESC 测定中测试与 1 结构相关的化合物作为心肌细胞诱导剂，以及 2) 在经过验证的人 ESC 心肌细胞分化测定中测试目标 1 中鉴定的有效化合物。基于我们令人鼓舞的初步结果，成功完成拟议工作将提供一个廉价的试剂工具箱，可用于从生物技术意义上的人类 ESC 诱导心肌细胞。以这种方式制备人心肌细胞将提供大量心肌细胞，并将广泛用于CRO、生物技术或大型制药行业，以帮助患有包括心肌梗塞在内的心力衰竭的个体以及用人心肌细胞进行药物安全性测试减少不良药物相互作用并开发更安全的药物。 公众健康相关性：对于心脏病发作患者来说，干细胞疗法可能提供一种再生受损心肌细胞的方法。目前的疗法只能改善心脏功能。我们工作的目标是利用化学生物学来开发小分子“工具箱”化合物，以刺激干细胞分化并产生心肌细胞。最终，这项工作的结果将提供用于培养心肌细胞的试剂，用于治疗心脏病的生物技术过程。