Biological Correlation and Analysis

生物学关联与分析

• 批准号: 7921384
• 负责人: STEVEN M SWANSON
• 金额: $ 24.83万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7921384
• 关键词: Animal Model; Antineoplastic Agents; Apoptosis; Biological; Biological Assay; Cell Cycle Arrest; Cells; Chemicals; Collaborations; Complex Mixtures; Dose; Enzymes; Evaluation; Fiber; Foundations; HL60; Hela Cells; Histone Deacetylase; Immunodeficient Mouse; Induction of Apoptosis; Molecular; Molecular Target; Mus; Natural Product Drug; Pharmacology; Solid; Source; Testing; Therapeutic Index; Toxic effect; Work; base; drug discovery; in vivo; multicatalytic endopeptidase complex; overexpression; programs; research study; tumor xenograft

_ , ...... =5 -;, . Core A will focus on biological evaluation of extracts, chromatograpnic'fractions,'and pure isolates prepared by all of the projects within the program in order to help prioritize subsequent biological and chemical work. This strategy of using bioassay-guided isolation will afford us the opportunity to pursue biological activity within complex mixtures. Extracts found active by Core A will be further purified by Projects 1-3 (OSU, UIC, and RTI, respectively) and the pure isolates returned to us for further analysis. Promising pure compounds will ultimately be further tested in animal models to assess efficacy and toxicity. Mechanism of action studies will be conduced to study the molecular pharmacology of pure compounds with the most favorable therapeutic indices. The Leader of Core A has well-established collaborations with all of the Project Leaders of this Program Project and has previously employed a variety of assays for natural product drug discovery. Our ongoing working relationships with other Projects and Cores and our ability to develop new biological assays as needed will assure that Core A is fully integrated in the program project and serves all projects therein. The Specific Aims for Core A are to (1) conduct molecular-target based assays including the histone deacetylase assay (HDAC) and inhibition of the 20S proteasome. These assays will be conducted initially on extract of materials Our second specific aim is to follow active leads identified by initial analysis using cell based assays such as HL60, which is known to overexpress the 20S proteasome, or HeLa cells that are the source of the HDAC used in the molecular target assays. Our third specific aim is to assess the activity of our most promising active pure compounds in vivo. These experiments will include initial dose ranging studies followed by efficacy studies using the hollow fiber assay or tumor xenografts studies in immunodeficient mice. Finally, studies will be performed on those pure compounds that prove to be effective anticancer agents with limited toxicity. in mice. These studies will focus on determining the mechanism of action and may include studies such as pathway of apoptosis induction or mechanism of cell cycle arrest. The biological assays outlined in this Core, used in concert with Cores B through D, will provide a solid foundation of support for all the Projects within the program.

_，......=5-；，。 核心A将侧重于提取物、色谱组分和制备的纯分离物的生物学评价 通过该计划内的所有项目，以帮助确定后续生物和化学工作的优先顺序。 这种利用生物测定指导分离的策略将为我们提供追求生物活动的机会。 在复杂的混合物中。被核心A发现具有活性的提取物将由项目1-3进一步提纯(OSU，UIC， 和RTI)和纯分离物返回我们进行进一步分析。前景看好的纯化合物 最终将在动物模型中进一步测试，以评估疗效和毒性。行动研究的机制 将有助于研究纯化合物的分子药理学最有利的 治疗指标。核心A的领导与所有项目领导建立了良好的合作关系 该计划项目的一部分，此前曾采用多种分析方法用于天然产物药物的发现。 我们与其他项目和核心的持续工作关系以及我们开发新生物的能力 根据需要进行的分析将确保核心A完全集成到计划项目中，并为所有项目服务 在那里。核心A的具体目标是(1)进行基于分子靶标的分析，包括组蛋白 脱乙酰酶试验(HDAC)和抑制20S蛋白酶体。这些化验将首先在 材料提取我们的第二个特定目标是追踪通过使用cell进行初步分析而确定的有效线索 基于HL60的检测，已知的是过度表达20S蛋白酶体，或HeLa细胞 用于分子靶标分析的HDAC的来源。我们的第三个具体目标是评估 我们体内最有前景的活性纯化合物。这些实验将包括初始剂量范围 随后的研究是使用中空纤维试验的有效性研究或肿瘤移植研究 免疫缺陷小鼠。最后，将对那些被证明有效的纯化合物进行研究 毒性有限的抗癌药。在老鼠身上。这些研究将集中在确定其作用机制。 作用，并可能包括研究，如诱导凋亡的途径或细胞周期停滞的机制。 本核心中概述的生物分析，与B到D核心一起使用，将提供 为计划内的所有项目提供支持的基础。