cAMP signaling in melanoma pathogenesis: Evidence for multiple microdomains playi

黑色素瘤发病机制中的 cAMP 信号传导：多个微域发挥作用的证据

• 批准号: 8294711
• 负责人: Jonathan Hale Zippin
• 金额: $ 17.12万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294711
• 关键词: Adenylate Cyclase; Basic Science; Benign; Beta Cell; Bicarbonate Ion; Bicarbonate Ions; Binding Proteins; Biological; Biology; Biopsy; CREB1 gene; Calcium; Cell Line; Cell Nucleus; Cell membrane; Cells; Cessation of life; Chemicals; Chemotaxis; Clinical Trials; Collaborations; Contact Inhibition; Critiques; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytoplasm; Data; Dermatology; Development; Diagnosis; Education; Forskolin; Funding; GTP-Binding Proteins; Genes; Genetic; Genome; Glucose; Goals; Golgi Apparatus; Growth; Growth Cones; Human; In Vitro; Individual; Institution; Intervention; Investigation; Journals; Knowledge; Lead; Lesion; Malignant Neoplasms; Mammalian Cell; Manuscripts; Medical; Medical center; Melanoma Cell; Memorial Sloan-Kettering Cancer Center; Mentors; Methods; Mitochondria; Modeling; Mus; NIH 3T3 Cells; Neoplasm Metastasis; Nerve Growth Factors; Neurons; Nevus; Nuclear; Oncogenes; PC12 Cells; PI3K/AKT; Pathogenesis; Pathway interactions; Physicians; Play; Protein Isoforms; Proteins; Publications; Ras/Raf; Reagent; Relative (related person); Reporting; Research; Research Personnel; Resources; Role; Scientist; Secure; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Source; Techniques; Training; Work; Writing; analog; anticancer research; base; calcium bicarbonate; effective therapy; genetic inhibitor; improved; inhibitor/antagonist; keratinocyte; medical schools; meetings; melanocyte; melanoma; microphthalmia-associated transcription factor; migration; new therapeutic target; novel; skills; skin disorder; small molecule; transcription factor; tumor; unpublished works

DESCRIPTION (provided by applicant): I have spent the last ten years building an expertise in the study of cAMP microdomains, specifically those regulated by the novel protein soluble adenylyl cyclase (sAC). During my training in dermatology, I applied the techniques and skills I have developed to the understanding of hyper proliferative keratinocyte skin disease, which led to a recent publication in the Journal of Investigative Dermatology. Over the past year, I began to explore the role of cAMP signaling in melanoma. I have developed two fruitful collaborations with experts in melanoma biology, Dr. Wolchok and Dr. Bastian at Memorial Sloan Kettering Cancer Center (MSKCC), and have continued my collaboration with an expert in sAC biology, Dr. Buck. Dr. Bastian and Dr. Buck will serve as my mentors during my training, and Dr. Wolchok will serve as an advisor. Over the next five years, I will have the privilege of being trained at both a world-class cancer research institution, MSKCC, and a leading medical college, Weill Cornell Medical Center (WCMC), both located at one of the most prestigious research corners in the world (WCMC/MSKCC/Rockefeller), proximity to which allows for unprecedented resources and exposure. Over the next five years, I have formulated a plan to further my expertise in cAMP signaling and develop my knowledge in melanoma biology. My short- term plan is to continue my education in order to become a physician scientist in dermatology. My long-term goal, in five years, is to secure R01 funding as an independent investigator. Melanoma is the sixth most common human cancer and one of the deadliest. Once melanoma spreads beyond the skin, effective medical interventions are limited. While certain signaling pathways, such as the Ras/Raf/ERK pathway, have well- established roles in controlling melanoma pathogenesis, recent clinical trials and basic science reports suggest that blocking this pathway alone is an insufficient treatment for melanoma. It has become apparent that the development of an effective treatment for melanoma relies on an improved understanding of the intricacies of melanoma signaling. cAMP has been implicated in a variety of signaling pathways that are key to the development and pathogenesis of melanoma, but in many cases the source and ramifications of cAMP signaling is poorly understood. A new class of adenylyl cyclases called soluble adenylyl cyclase (sAC) was recently characterized, and I was involved in developing a cadre of novel small molecule and genetic inhibitors capable of differentiating sAC-generated and the canonical G-protein sensitive transmembrane adenylyl cyclase (tmAC)-generated cAMP. In the past, I have used these reagents to establish the role of sAC in nerve growth factor-induced Rap activation in PC-12 cells, netrin-induced growth cone chemotaxis in primary neurons, and glucose-induced cAMP in beta cells. In each of these cases, involvement of cAMP was known, but a suitable model to explain its role was lacking. By differentiating tmAC- from sAC-dependent cAMP, more coherent models have been developed. I have applied these techniques to melanoma biology and have found that sAC protein migrates into the nucleus in human melanocytic proliferations as melanocytes acquire cellular atypical. In the past, I demonstrated that nuclear sAC activates the cAMP responsive binding protein transcription factor. I have also discovered that sAC protein is upregulated in melanoma, and inhibitors of sAC block melanocyte growth. In this proposal I plan to evaluate the relative contributions of sAC and tmAC microdomains in melanoma pathogenesis. I predict that this line of investigation will lead to novel therapeutic targets of melanoma.!

描述（由申请人提供）：过去十年，我一直在研究 cAMP 微结构域，特别是那些受新型蛋白质可溶性腺苷酸环化酶 (sAC) 调节的微结构域，积累了专业知识。在皮肤病学培训期间，我应用了自己掌握的技术和技能来了解过度增殖性角质形成细胞皮肤病，这导致了最近在《皮肤病学研究杂志》上发表的一篇文章。在过去的一年里，我开始探索cAMP信号在黑色素瘤中的作用。我与纪念斯隆凯特琳癌症中心 (MSKCC) 的黑色素瘤生物学专家 Wolchok 博士和 Bastian 博士开展了两次富有成效的合作，并继续与 sAC 生物学专家 Buck 博士合作。 Bastian博士和Buck博士将在我的培训期间担任我的导师，Wolchok博士将担任顾问。在接下来的五年里，我将有幸在世界一流的癌症研究机构 MSKCC 和领先的医学院威尔康奈尔医学中心 (WCMC) 接受培训，这两个机构都位于最负盛名的研究角落之一世界上最大的中心（WCMC/MSKCC/洛克菲勒），靠近这些中心可以提供前所未有的资源和曝光度。在接下来的五年中，我制定了一项计划，以进一步提升我在 cAMP 信号传导方面的专业知识，并发展我在黑色素瘤生物学方面的知识。我的短期计划是继续接受教育，成为一名皮肤科医师科学家。我五年内的长期目标是作为独立研究者获得 R01 资助。黑色素瘤是第六种最常见的人类癌症，也是最致命的癌症之一。一旦黑色素瘤扩散到皮肤之外，有效的医疗干预措施就会受到限制。虽然某些信号通路（例如 Ras/Raf/ERK 通路）在控制黑色素瘤发病机制中具有明确的作用，但最近的临床试验和基础科学报告表明，单独阻断该通路不足以治疗黑色素瘤。显然，黑色素瘤有效治疗方法的开发依赖于对黑色素瘤信号传导复杂性的深入了解。 cAMP 涉及多种信号通路，这些信号通路对于黑色素瘤的发展和发病机制至关重要，但在许多情况下，人们对 cAMP 信号通路的来源和后果知之甚少。最近，人们对一类新的腺苷酸环化酶进行了表征，称为可溶性腺苷酸环化酶 (sAC)，我参与了一系列新型小分子和基因抑制剂的开发，这些抑制剂能够区分 sAC 生成的腺苷酸环化酶和典型的 G 蛋白敏感跨膜腺苷酸环化酶 (tmAC) )-生成cAMP。过去，我曾使用这些试剂来确定 sAC 在 PC-12 细胞中神经生长因子诱导的 Rap 激活、原代神经元中 netrin 诱导的生长锥趋化性以及 β 细胞中葡萄糖诱导的 cAMP 中的作用。在每一个案例中，cAMP 的参与都是已知的，但缺乏合适的模型来解释其作用。通过区分 tmAC 和 sAC 依赖性 cAMP，已经开发出更一致的模型。我将这些技术应用于黑色素瘤生物学，并发现当黑色素细胞获得细胞非典型性时，sAC 蛋白在人类黑色素细胞增殖中迁移到细胞核中。过去，我证明了核 sAC 激活 cAMP 反应性结合蛋白转录因子。我还发现 sAC 蛋白在黑色素瘤中表达上调，并且 sAC 抑制剂可阻止黑色素细胞生长。在本提案中，我计划评估 sAC 和 tmAC 微结构域在黑色素瘤发病机制中的相对贡献。我预测这一研究方向将带来黑色素瘤的新治疗靶点。！