Discovery of Inhibitors of PTH-Wnt Signaling Synergy in Bone Cells

骨细胞中 PTH-Wnt 信号协同抑制剂的发现

• 批准号: 8000306
• 负责人: Erik Mills Schwiebert
• 金额: $ 23.43万
• 依托单位: DISCOVERYBIOMED, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8000306
• 关键词: Accounting; Affect; Aging; Alabama; Arthritis; Award; Biological; Biological Assay; Biological Factors; Bone Resorption; Bone Tissue; Cell Count; Cell Line; Cell membrane; Cells; Collaborations; Collection; Complex; Cost of Illness; Cytolysis; Dependence; Disease; Dose; Equilibrium; Firefly Luciferases; Foundations; Future; Genetic Transcription; Goals; Hand; Health Care Costs; Healthcare Industry; Housing; Human; Incidence; Individual; Lead; Legal patent; Light; Marketing; Methods; Molecular; Monitor; Musculoskeletal; NIH Program Announcements; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Osteoblasts; Osteoclasts; Osteogenesis Imperfecta; Osteoporosis; Outcome; Parathyroid Hormones; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Physiology; Phytochemical; Plant Roots; Play; Population; Preclinical Drug Evaluation; Primary Bone Osteosarcoma; Process; Publications; Rattus; Renilla; Reporter; Research; Research Personnel; Role; Screening procedure; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Standardization; Structure; TCF Transcription Factor; Testing; Therapeutic; Time; Toxic effect; Transfection; United States National Institutes of Health; Universities; Validation; WNT Signaling Pathway; Work; aged; aging population; assay development; base; bone; bone cell; bone loss; cheminformatics; design; drug discovery; drug market; forging; high throughput screening; human PTH protein; inhibitor/antagonist; innovation; interest; luminescence; miniaturize; novel; osteosarcoma; pharmacophore; prevent; programs; public health relevance; receptor; research study; response; scaffold; skin disorder; small molecule; tool; transcription factor

DESCRIPTION (provided by applicant): Project Summary Description Title: Discovery of Inhibitors of PTH-Wnt Signaling Synergy in Bone Cells. Osteoporosis is a growing problem in the aged and an unfortunately large disease market and burden to the healthcare industry. This debilitating disease costs $18 billion in healthcare costs annually in the US and affects 10 million people in the US and an estimated 100 million worldwide. Brittle bone disease is expected to increase in incidence in the years to come due to an aging US and worldwide population. DiscoveryBioMed, Inc., the University of Alabama at Birmingham (UAB) Research Foundation, and Dr. Xu Cao (a world renowned bone cell signaling researcher previously with UAB and currently with Johns Hopkins) has forged a research collaboration to discover small molecule therapeutics that prevent osteoporosis. DBM has developed a light-based assay to find inhibitors of synergistic parathyroid hormone (PTH) and Wnt signaling pathways. DBM seeks to "multiplex" this high-throughput screening (HTS) friendly bioassay with additional light-based endpoints in cellular lysates and in the supernatant collected before cell lysis to monitor a series of endpoints relevant to osteoporosis drug discovery. Most importantly, this screening program utilizes a mammalian bone cell line as the biologically relevant cellular platform. Milestone 1 of this program seeks to fully design and optimize each individually light-based assay for each desired biological endpoint. Milestone 2 seeks to "multiplex" each individual assay into one powerful primary HTS bioassay. Milestone 3 seeks to screen the first 20,000 small molecules from a diverse set of synthetic organic compounds and natural product-derived phytochemicals. As a transition to planned Phase 2 research, DBM will assess hit-to-lead compounds early and often with cheminformatics tools to identify commonality in structure among the hit small molecules. This process allows parallel targeted work on lead compounds of interest already identified, while random screening proceeds. DBM will apply its core principles of drug discovery to this program that include: (a) screening on a biologically relevant cell platform (i.e., bone cells); (b) screening with both targeted and phenotypic intent and endpoints; (c) screening each test small molecule in triplicate to provide biostatistical power to the primary HTS experiment; and (d) assessing multiple high-content endpoints in primary HTS bioassay and in carefully scripted secondary validation experiments with Dr. Cao's research group. Based on the work accomplished thus far, DBM anticipates a strong outcome from this osteoporosis drug discovery program. PUBLIC HEALTH RELEVANCE: Public Health Relevance Statement Osteoporosis is a $ billion burden to the healthcare industry, with 10 million people affected in the US and an estimated 100 million affected worldwide. "Brittle bone disease" is expected to increase in incidence in the years to come due to an aging US and worldwide population. DiscoveryBioMed, Inc., the UAB Research Foundation, and Dr. Xu Cao and coworkers from Johns Hopkins have formed a triangular research collaboration to find new small molecule therapeutics to control and cure osteoporosis that work at the cellular and molecular level within bone tissue.

描述（申请人提供）：项目摘要描述标题：发现骨细胞中PTH-WNT信号传导协同作用的抑制剂。骨质疏松症是老年人和不幸的疾病市场的日益严重的问题，也是医疗保健行业的负担。这种使人衰弱的疾病每年在美国每年的医疗保健费用为180亿美元，在美国影响1000万人，估计在全球范围内估计1亿人。预计由于美国和全球人口老龄化，预计在未来几年的发病率将增加。伯明翰（UAB）研究基金会阿拉巴马大学的DiscoveryBiomed，Inc。和Xu Cao博士（Xu Cao博士（一名以前曾与UAB一起在UAB和Johns Hopkins与Johns Hopkins一起使用的世界著名的骨细胞信号研究人员）进行了一项研究合作，以发现小分子疗法，该协作该研究人员预防骨质疏松症。 DBM开发了一种基于光的测定法，以发现协同甲状旁腺激素（PTH）和Wnt信号通路的抑制剂。 DBM试图“多重”这种高通量筛选（HTS）友好的生物测定，并在细胞裂解物中以及在细胞裂解前收集的上清液中具有其他基于光的终点，以监测与骨质疏松药物相关的一系列端点。最重要的是，该筛查程序利用哺乳动物骨细胞系作为生物学相关的细胞平台。该计划的里程碑1旨在为每个所需的生物终点完全设计和优化每个单独的基于光的测定法。 Milestone 2试图将每个单独的测定方法“多重”“多重”成一个强大的主要HTS生物测定。 Milestone 3试图从各种合成有机化合物和天然产物衍生的植物化学物质中筛选前20,000个小分子。作为对计划2阶段研究的过渡，DBM将尽早评估命中至铅化合物，并且通常使用化学信息学工具来识别命中小分子之间的结构中的通用性。该过程允许对已经确定的感兴趣的铅化合物进行并行针对的工作，而随机筛选进行了进行。 DBM将将其药物发现的核心原理应用于该程序，其中包括：（a）在生物学相关的细胞平台上筛选（即骨细胞）； （b）具有靶向和表型意图和终点的筛选； （c）筛选每个测试的小分子一式三份，以为主要HTS实验提供生物统计能力； （d）在主要HTS生物测定中评估多个高质量终点，并在CAO博士的研究小组中进行了精心脚本的辅助验证实验。基于迄今为止所完成的工作，DBM预计该骨质疏松药物发现计划会取得很大的结果。 公共卫生相关性：公共卫生相关性声明骨质疏松症对医疗保健行业负担$ 10亿美元，在美国受影响1000万人，估计在全球范围内受到了1亿次影响。由于美国和全球范围内的老龄化，预计“脆性骨病”将在未来几年内增加。 DiscoveryBiomed，Inc。，UAB研究基金会以及Johns Hopkins的Xu Cao博士和同事形成了三角研究合作，以发现新的小分子疗法来控制和治愈骨组织中细胞和分子水平的骨质疏松症。