Isoxazole Small Molecules That Induce Stem Cell Differentiation

诱导干细胞分化的异恶唑小分子

• 批准号: 8205396
• 负责人: Hector Ruben Aguilar
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205396
• 关键词: Adult; Aftercare; Agonist; American Heart Association; Azoles; Behavior; Biological; Biological Assay; Biological Process; Biology; Cardiac; Cardiovascular Diseases; Cause of Death; Cell Therapy; Cessation of life; Characteristics; Chemistry; Cicatrix; Collaborations; Coupling; Data; Fibrosis; Foundations; Future; G-Protein-Coupled Receptors; GPR68 gene; Goals; Health; Heart; Heart Diseases; Heart Transplantation; Image; Immune system; In Vitro; Isoxazoles; Knowledge; Laboratories; Lead; Libraries; Life; Life Style; Literature; Luciferases; Measures; Medical center; Methodology; Muscle; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Nature; Organ; Organic Chemistry; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Pluripotent Stem Cells; Population; Quality of life; Radiolabeled; Reader; Reporter Genes; Reporting; Research; Risk; Role; Running; Stem cells; Structure-Activity Relationship; Testing; Texas; Tissues; United States; Universities; analog; base; burden of illness; cardiogenesis; design; disability; drug discovery; heart function; high risk; in vivo; mortality; prophylactic; radiotracer; regenerative; repaired; small molecule; small molecule libraries; statistics; stem; stem cell differentiation; stem cell population; tool

DESCRIPTION (provided by applicant): About 1 in every 6 deaths in the United States is due to heart disease resulting in heart attack (myocardial infraction, MI). Patients who survive a heart attack suffer permanent damage to the heart and carry a higher risk of mortality. Stem cell based therapies provide a new tool towards cardiac repair and regeneration that can ultimately enhance health, lengthen life, and reduce the burdens of illness and disability for patients post MI. This proposal is geared towards conducting research at the interface of chemistry and biology with the long term objective to identify drug-like molecules with the ability to induce an endogenous population of stem cells in the adult heart toward cardiac repair post MI. Through extensive research, a lead molecule able to deter the formation of scar tissue (fibrosis) and regenerate heart muscle post MI has been identified. The goal of this proposal is to expand the small molecule library to identify new lead compounds with increased potency and utilize them in synthesizing probes to confirm the biological target as well as seek fundamental knowledge about the nature and behavior of stem cell differentiation. This will in turn set the foundation and basic biological understanding to develop molecules with more drug like characteristics using a more rational approach. To accomplish this goal the following aims are proposed: (1) Design, synthesize, and evaluate analogues of our current lead molecule (2) Evaluate biological data and synthesize photolabeled or radiolabeled probes from lead molecules that can confirm the biological target and assist in the understanding of biological processes and mechanisms involved in stem cell differentiation. Al molecules will be synthesized using cross coupling chemistry reported in the literature and developed in our laboratory. The biological activity will be evaluated through luciferase reporter gene assays. PUBLIC HEALTH RELEVANCE: Cardiovascular disease (CVD) resulting in heart attack (myocardial infarction or MI) is the most common and costly cause of death in the modern world. Patients who survive a heart attack suffer permanent damage to the heart and thus patients are forced to make drastic changes in their lifestyles and carry a higher risk of mortality. Stem cell based therapies provide a new tool towards cardiac repair and regeneration that ultimately enhance health, lengthen life, and reduce the burdens of illness and disability for patients post MI.

描述（由申请人提供）：在美国，大约每 6 例死亡中就有 1 例是由于心脏病导致心脏病发作（心肌梗死，MI）。心脏病发作后幸存的患者心脏会遭受永久性损伤，死亡风险更高。基于干细胞的疗法为心脏修复和再生提供了一种新工具，最终可以增强心梗后患者的健康、延长寿命并减轻疾病和残疾负担。该提案旨在开展化学和生物学交叉领域的研究，长期目标是鉴定能够诱导成人心脏内源性干细胞群进行心肌梗死后心脏修复的药物样分子。通过广泛的研究，已经确定了一种能够阻止疤痕组织（纤维化）形成和心肌梗死后心肌再生的先导分子。该提案的目标是扩展小分子库，以识别具有更高效力的新先导化合物，并利用它们合成探针来确认生物靶标，并寻求有关干细胞分化的性质和行为的基础知识。这反过来将为使用更合理的方法开发具有更多类似药物特征的分子奠定基础和基本的生物学理解。为了实现这一目标，提出了以下目标：（1）设计、合成和评估我们当前先导分子的类似物（2）评估生物数据并从先导分子合成光标记或放射性标记探针，这些探针可以确认生物靶标并帮助理解干细胞分化所涉及的生物过程和机制。 Al 分子将使用文献中报道并由我们实验室开发的交叉耦合化学合成。生物活性将通过荧光素酶报告基因测定进行评估。 公共卫生相关性：导致心脏病发作（心肌梗塞或 MI）的心血管疾病 (CVD) 是现代世界最常见且代价最高的死因。心脏病发作后幸存的患者心脏会受到永久性损伤，因此患者被迫彻底改变生活方式，并面临更高的死亡风险。基于干细胞的疗法为心脏修复和再生提供了一种新工具，最终可以增强心梗后患者的健康、延长寿命并减轻疾病和残疾负担。