Small Molecules Targeting the Mitochondrial Permeability Transition

针对线粒体通透性转变的小分子

• 批准号: 8435345
• 负责人: Dennis Neil Bourdette
• 金额: $ 3.06万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435345
• 关键词: Affinity Chromatography; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Biological; Biological Assay; Brain; Castes; Cell Death; Cells; Chemicals; Chemistry; Collaborations; Collagen Type VI; Disease; Exhibits; Future; Genomics; Goals; Heart; Human; In Situ; In Vitro; Inner mitochondrial membrane; Ion Channel; Laboratories; Letters; Medical Research; Mitochondria; Modeling; Molecular; Molecular Bank; Molecular Structure; Morphologic artifacts; Multiple Sclerosis; Mus; Muscular Dystrophies; Myocardial Infarction; Nature; Organelles; Outcome; Pathology; Pathway interactions; Permeability; Pharmaceutical Preparations; Physiological; Play; Process; Production; Program Development; Property; Proteins; Publications; Regulation; Reperfusion Injury; Research Institute; Research Personnel; Resistance; Resources; Staging; Stroke; Structure; Therapeutic; United States National Institutes of Health; base; clinically significant; contextual factors; design; high throughput screening; human disease; improved; in vitro Assay; inhibitor/antagonist; insight; mitochondrial dysfunction; mitochondrial permeability transition pore; novel; novel strategies; novel therapeutics; repository; screening; small molecule; stem; therapeutic target

DESCRIPTION (provided by applicant): Activation of the mitochondrial permeability transition pore (PTP) clearly plays a key role some of the most wide-spread and therapeutically challenging human diseases. Our studies have established that the PTP operates in two modes 1) transiently, whereby the PTP acts as a mitochondrial Ca2+ release channel or 2) persistently, which ultimately results in the cell death and disease. Although well characterized on a functional level, we have no small molecules that specifically target the PTP or the transition from transient to persistent - from normal to pathological. As a result, our goal in this applicatin is to use the resource available in the MLPCN network is to identify the probes that uniquely target the PTP. This information is critical if we are to be able to effectively identify and/or design valuable therapeutics targeting the transition of the PTP from normal to pathological. The specific objectives of this application are based in the synergy possible through the unique combination of novel approaches available in our three laboratories; Aim 1 - We will screen the available NIH SMR to identify small molecule probes able to inhibit PTP opening using a simple in vitro assay that has already been adapted to the 1536 plate format to allow screening in high throughput (HTS) formats. Aim 2 - Since the primary screen is designed to "caste a wide net", secondary screens have been developed that can also be used in HTS formats to limit to our future studies to molecules that specifically target the PTP. Aim 3 - We will initiate studies on te mechanism of action of active compounds based on assays of mitochondrial function as assessed in an in situ, whole cell context. These tertiary screens will also serve as a mechanism to assess chemically modified active compounds in an attempt to improve their biological activity. These studies will set the stage for future interrogation aimed at extending our understanding of mitochondria and PTP activity in physiological and pathological settings. Clearly, these outcomes will be fundamental to developing novel therapeutic strategies specifically targeting the pore in the many disease processes in which the PTP has been clearly implicated.

描述（由申请人提供）：线粒体通透性过渡孔（PTP）的激活清楚地起着一些关键作用，其中一些最广泛，最具挑战性的人类疾病。我们的研究已经确定，PTP以两种模式运行1）瞬时，PTP充当线粒体Ca2+释放通道或2）持久，最终导致细胞死亡和疾病。尽管在功能水平上表征良好，但我们没有小分子，这些分子专门针对PTP或从瞬态到持久性的过渡 - 从正常到病理。结果，我们在此应用程序中的目标是使用MLPCN网络中可用的资源是确定针对PTP的唯一探针。如果我们能够有效地识别和/或设计针对PTP从正常情况过渡到病理的有价值的治疗剂，那么此信息至关重要。该应用程序的特定目标是通过我们三个实验室中可用的新颖方法的独特组合来基于协同作用的； AIM 1-我们将筛选可用的NIH SMR，以鉴定能够使用已经适应1536板格式的简单体外测定方法来抑制PTP开口的小分子探针，以允许以高吞吐量（HTS）格式进行筛选。 AIM 2-由于主要屏幕旨在“种姓宽网”，因此已经开发了辅助屏幕，该屏幕也可以以HTS格式使用，以将我们未来的研究限制为专门针对PTP的分子。 AIM 3-我们将根据在原位，全细胞环境中评估的线粒体功能的测定法对活动化合物的作用机理进行研究。这些三级筛选还将作为评估化学改良活性化合物的一种机制，以改善其生物学活性。这些研究将为未来的审讯奠定阶段，旨在扩展我们对生理和病理环境中的线粒体和PTP活性的理解。显然，这些结果将是制定新型的治疗策略的基础，这些治疗策略是针对PTP明显涉及的许多疾病过程中毛孔的专门针对毛孔的。