Isoxazole Small Molecules That Induce Stem Cell Differentiation

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的心脏病发作（心肌梗死，MI）。心脏病发作后存活下来的患者会对心脏造成永久性损伤，死亡风险也更高。干细胞疗法为心脏修复和再生提供了一种新的工具，最终可以增强健康，延长寿命，并减少心肌梗死后患者的疾病和残疾负担。该提案旨在进行化学和生物学界面的研究，其长期目标是鉴定具有诱导心肌梗死后成人心脏内源性干细胞群体的药物样分子。通过广泛的研究，已经确定了一种能够阻止心肌梗死后瘢痕组织（纤维化）形成和心肌再生的先导分子。本课题的目标是扩大小分子文库，以鉴定新的先导化合物，并利用它们合成探针来确认生物靶点，以及寻求有关干细胞分化性质和行为的基础知识。反过来，这将为使用更合理的方法开发具有更多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，我们提出了以下目标：(1)设计、合成和评估我们目前的铅分子的类似物；(2)评估生物学数据并合成来自铅分子的光标记或放射性标记探针，这些探针可以确认生物靶标，并有助于理解干细胞分化的生物过程和机制。本实验室将利用文献报道的交叉偶联化学合成Al分子。生物活性将通过荧光素酶报告基因检测进行评估。

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.