CAMP--ROLE IN GROWTH DIFFERENTIATION AND NEOPLASIA

腺苷3‘：5’一磷酸(CAMP)在调节中起着关键作用 细胞生长、基因表达和新陈代谢。有目的地调节 细胞功能已通过目前的药理工具实现 可用于操纵细胞内cAMP水平，但其众多 缺点限制了这种方法的实际治疗应用。 否则很有希望的原则。我们最近一直在与一个独特的 毒素，由百日咳波氏杆菌精心研制，是一种侵入性 腺苷环化酶。这种酶会穿透人体吞噬细胞并 在那里产生了史无前例的营地。因为它的 独特的机制和效力，这种毒素似乎是一种很有前途的工具 研究cAMP在生长和生长调节中的作用 差异化。事实上，初步工作证明了这一能力 毒素导致三种肿瘤哺乳动物细胞内cAMP大幅升高 在每种情况下，伴随的生长抑制、分化或 减少了生物检测中的恶意行为。建议数 研究人员将使用这种新型毒素来检查大型cAMP的影响 正常造血细胞生长和表型表达水平的升高 前体和转化细胞中。我们将更全面地描述 先前在肿瘤细胞中发现的表型改变的性质 并确定它们与体内改变的肿瘤行为的关系。 在追求这些调查目标时，候选人将利用他的 既往的造血和肿瘤细胞培养经验 技巧。此外，他将立即获得越来越多的 纯化的毒素制剂和毒素功能的新信息 他与那些最先 阐明了其作用机制。最后，他将享受专家的指导 相关学科的研究和一名高级研究员的赞助 已证明有能力促进独立调查人员的发展。 这些研究将提供对cAMP和 哺乳动物细胞的表型表达。此外，他们还将展示 这种毒素作为一种工具用于研究cAMP在体内的作用 细胞功能的调节。

Adenosine 3':5' monophosphate (cAMP) plays a pivotal role in the regulation of cell growth, gene expression, and metabolism. Purposeful modulation of cellular function has been achieved with the pharmacologic tools currently available for manipulating intracellular cAMP levels, but their numerous drawbacks have limited the practical therapeutic application of this otherwise promising principle. We have recently been working with a unique toxin, elaborated by Bordetella pertussis bacteria, which is an invasive adenylate cyclase. This enzyme will penetrate human phagocytes and generate therein unprecedented amounts of cAMP. Because of its unique-mechanism and potency, this toxin seems a promising tool for investigating the role of cAMP in regulation of growth and differentiation. Indeed, preliminary work documents the abililty of this toxin to cause large cAMP elevations in three neoplastic mammalian cell lines; in each case, concomitant growth inhibition, differentiation, or decreased maligant behavior in biologic assays occurs. The proposed research will employ this novel toxin to examine the effects of large cAMP elevations on growth and phenotypic expression in normal hematopoietic precursors and in transformed cells. We will characterize more fully the nature of the phenotypic alterations previously noted in neoplastic cells and determine their relationship to altered neoplastic behavior in vivo. In pursuing these investigative goals, the candidate will exploit his previous experience in hematopoetic and neoplastic cell culture techniques. Moreover, he will have immediate access to progressively more purified toxin preparations and new information on toxin function as a result of his close collaborative relationship with those who first elucidated its mechanism. Finally, he will enjoy the guidance of experts in relevant disciplines and the sponsorship of a senior researcher with a proven ability to foster the development of independent investigators. These studies will offer insights into the relationship between cAMP and phenotypic expression in mammalian cells. Moreover, they will demonstrate the utility of this toxin as a tool for investigating the role of cAMP in the regulation of cellular functions.