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)：项目概要描述标题：在骨细胞中发现甲状旁腺激素-Wnt信号协同的抑制剂。骨质疏松症是一个日益严重的老年人问题，不幸的是，它是一个巨大的疾病市场，也是医疗保健行业的负担。这种令人衰弱的疾病在美国每年造成180亿美元的医疗成本，影响着美国的1000万人和全球约1亿人。由于美国和全球人口老龄化，脆性骨病的发病率预计在未来几年将会增加。DiscoveryBioMed，Inc.、阿拉巴马大学伯明翰分校(UAB)研究基金会和世界著名的骨细胞信号转导研究员徐曹博士(曾在UAB工作，目前在约翰斯·霍普金斯大学工作)达成了一项研究合作，以发现预防骨质疏松的小分子疗法。DBM已经开发了一种基于光的测试来寻找协同甲状旁腺激素(PTH)和Wnt信号通路的抑制剂。DBM寻求将这种高通量筛选(HTS)友好的生物测定与细胞裂解产物和细胞裂解前收集的上清液中的额外基于光的端点进行多路传输，以监测与骨质疏松症药物发现相关的一系列端点。最重要的是，该筛选计划利用哺乳动物骨细胞系作为生物相关的细胞平台。该计划的里程碑1旨在为每个所需的生物终点充分设计和优化每个单独的基于光的检测。里程碑2寻求将每个单独的化验“多路”化为一个强大的初级HTS生物化验。里程碑3试图从一系列不同的合成有机化合物和天然产品衍生植物化学物质中筛选出第一批20,000个小分子。作为向计划的第二阶段研究的过渡，DBM将及早评估命中到领先的化合物，并经常使用化学信息学工具来识别受打击的小分子之间的结构共性。这一过程允许对已经确定的感兴趣的先导化合物进行平行的有针对性的工作，同时进行随机筛选。DBM将把其药物发现的核心原则应用于该项目，其中包括：(A)在生物相关的细胞平台(即骨细胞)上进行筛选；(B)根据靶向和表型意图和终点进行筛选；(C)筛选每个测试小分子一式三份，为主要的HTS实验提供生物统计学力量；以及(D)在一次HTS生物检测和与曹博士的研究小组精心编写的二次验证实验中评估多个高含量的终点。基于到目前为止完成的工作，DBM预计这一骨质疏松症药物发现计划将产生强劲的结果。 公共健康相关性：公共健康相关性声明骨质疏松症是医疗保健行业的10亿美元负担，美国有1000万人受到影响，全球估计有1亿人受到影响。由于美国和世界人口老龄化，“脆性骨病”的发病率预计将在未来几年增加。来自约翰·霍普金斯大学的DiscoveryBioMed，Inc.、UAB研究基金会和徐曹博士及其同事组成了一个三角研究合作伙伴，以寻找新的小分子疗法来控制和治疗骨质疏松症，这种疗法在骨组织内的细胞和分子水平上起作用。