CELLULAR INTERACTIONS OF BIOLOGICALLY ACTIVE AGENTS

生物活性剂的细胞相互作用

• 批准号: 6128861
• 负责人: MARC L SNAPPER
• 金额: $ 22.86万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6128861
• 关键词: Golgi apparatus; Porifera; analog; animal extract; antiinflammatory agents; chemical structure function; chemical synthesis; chemoprevention; copper; diphtheria toxin; drug screening /evaluation; hydrolase; immunosuppressive; intermolecular interaction; intracellular transport; isomer; membrane activity; methylation; prostaglandins; protein transport; quinones; ricin; terpenes; tissue /cell culture; vesicle /vacuole

Identifying the cellular components involved in viral infection, cancer, atherosclerosis, diabetes, arthritis, and neurodegenerative disease will generate new opportunities to combat these afflictions. Molecular events of the cell membrane play pivotal roles in a variety of these health concerns. In many cases, the identify of cellular machinery involved is not known. Through the use of structurally modified variants of biologically active natural products, the research objective is to (i) reveal important cellular interactions involved in membrane signaling and trafficking, (ii) provide a better understanding of the structure, function, and regulation of these cellular components, and (iii) identify new cellular entities that are useful targets fro controlling a number of diseases. (-)-Ilimaquinone, a sponge metabolite, has been used to gain a better understanding of vesicular trafficking. Ilimaquinone inhibits vesicle- mediated secretion through its interference with S- adenosylhomocysteinase. An enzyme in the activated methyl cycle. The proposed studies explore the ilimaquinone's interact with this important antiviral target, as well as to determine the specific methylation events regulating vesicle-mediated secretion. Similarly, the cellular interactions of the cacospongionolids will be determined to help understand their potent anti-inflammatory action. Likewise, insight into the physiological role of the icoprostanes, a newly discovered. class of membrane metabolites, will be achieved using functionalized derivatives of these endogenous molecules. These interdisciplinary studies will help identify interactions responsible for regulating various aspects of membrane trafficking and signaling. With a better description of these events, fundamentally new approaches for controlling disease through the selective interference of trafficking and signaling functions should become feasible. Inhibitors of trafficking could provide a new means of lowering cholesterol levels, inhibiting the first steps in viral infection, or regulating the secretion of the beta- amyloid protein. In a related matter, treatments for a wide range of other illnesses potentially could benefit from selective inhibitors of endocytosis. For instance, patients that are desensitized to ascertain drug therapy could benefit from compounds that inhibit the endocytotic down- regulation of the drug's receptor. For these reasons, further knowledge of the details of ligand interactions with membrane compounds should be of substantial benefit.

识别与病毒感染、癌症、动脉粥样硬化、糖尿病、关节炎和神经退行性疾病有关的细胞成分将为对抗这些疾病带来新的机会。细胞膜的分子事件在各种健康问题中起着关键作用。在许多情况下，所涉及的细胞机制的识别是未知的。通过使用具有生物活性的天然产物的结构修饰变体，研究目标是：(i)揭示涉及膜信号传导和运输的重要细胞相互作用，（ii）更好地了解这些细胞成分的结构、功能和调节，以及（iii）确定新的细胞实体，这些细胞实体是控制许多疾病的有用目标。（-）- ilimaquinone是一种海绵代谢物，已被用于更好地了解囊泡运输。依马喹酮通过干扰S-腺苷高半胱氨酸酶抑制囊泡介导的分泌。活化甲基循环中的一种酶本研究拟探讨伊利喹酮与这一重要抗病毒靶点的相互作用，并确定调节囊泡介导分泌的特定甲基化事件。类似地，海绵状脂质的细胞相互作用将被确定，以帮助了解其有效的抗炎作用。同样的，对icoprostanes的生理作用的洞察，一项新发现。一类膜代谢物，将利用这些内源性分子的功能化衍生物来实现。这些跨学科的研究将有助于确定负责调节膜运输和信号传导各个方面的相互作用。随着对这些事件的更好描述，通过选择性干扰贩运和信号功能来控制疾病的根本新方法应该是可行的。贩运抑制剂可以提供一种降低胆固醇水平、抑制病毒感染的第一步或调节β -淀粉样蛋白分泌的新方法。在一个相关的问题上，治疗范围广泛的其他疾病可能受益于选择性抑制内吞作用。例如，对药物治疗不敏感的患者可以从抑制药物受体内吞下调的化合物中获益。由于这些原因，进一步了解配体与膜化合物相互作用的细节应该是实质性的好处。