Generation of an UV-dependent Mouse Model of Melanoma

紫外线依赖性黑色素瘤小鼠模型的生成

• 批准号: 7430218
• 负责人: LIDIA KOS
• 金额: $ 10.21万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430218
• 关键词: 9p21; Address; Adult; CDKN2A gene; Cancer Biology; Cell Adhesion Molecules; Cell Line; Cells; Characteristics; Chromosomes; Complex; Condition; Cutaneous Melanoma; Data; Development; Disease; Dose; Endothelin; Endothelin Receptor; Endothelin-3; Environmental Risk Factor; Ethnology; Evaluation; Exposure to; Future; G-Protein-Coupled Receptors; Generations; Genetic; Goals; Human; In Vitro; Incidence; Intervention; Kinetics; Lead; Lesion; Ligands; Malignant - descriptor; Malignant Neoplasms; Mediating; Melanocytic Neoplasm; Melanoma Cell; Metalloproteases; Metastatic Melanoma; Modeling; Molecular; Molecular Target; Mus; Mutation; Neonatal; Neoplasm Metastasis; Numbers; Oncogenic; Pathogenesis; Pathway interactions; Personal Satisfaction; Phenotype; Pigments; Pilot Projects; Predisposition; Preventive; Process; Property; Protein Overexpression; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Skin; Skin Cancer; Solar Energy; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Transgenic Mice; Transgenic Organisms; Treatment Protocols; Ultraviolet Rays; base; host neoplasm interaction; keratinocyte; kindred; melanocyte; melanoma; migration; mouse model; mutant; novel; precursor cell; receptor; receptor coupling; tool; transcription factor; tumor; ultraviolet; ultraviolet irradiation

DESCRIPTION (provided by applicant): The malignant transformation of melanocytes, pigment producing cells, leads to the generation of melanoma. Cutaneous melanoma is the most lethal form of skin cancer and one of the fastest increasing cancers in the U.S. Melanomas are highly metastatic and current therapeutic interventions are not very effective. It is well established that the formation and progression of melanoma are influenced by genetic and environmental factors, as well as alterations in tumor-host interactions. Genetic studies have identified INK4a/ARF at chromosome 9p21 as a melanoma susceptibility locus. Amongst the environmental factors, exposure to the ultraviolet (UV) spectrum of solar radiation is considered to have a casual role in the majority of melanomas. The G-coupled receptor Endothelin receptor b (Ednrb) is considered a melanoma progression marker, and in vitro data suggest that its ligand, Endothelin 3 (Edn3), can alter the expression of adhesion molecules in melanoma cells. The goal of this study is to create a novel UV-dependent mouse model of melanoma based on the over-activation of the endothelin signaling pathway to address the functional relationship among UV, genetic factors and tumor-host interactions in melanoma pathogenesis. We will use an inducible transgenic mouse model we generated and characterized that produces excessive Edn3 throughout development, leading to the accumulation of large numbers of melanocytes in the skin of adult mice where they are not normally found. This condition is a result of a dramatic increase in the proliferation of precursors, which could also serve as the basis for melanocytic tumor formation. We will (1) evaluate whether a combination of neonatal UV exposure and the over-activation of the endothelin signaling pathway is sufficient for the generation of metastatic melanoma and (2) test for a role of ink4a/arf in UV-induced melanoma formation and progression in the Edn3 transgenic mice. The development of this new mouse model of melanoma has the potential to contribute to a better understanding of the complex ethnology of this disease and serve as a tool for the evaluation of effective preventive and therapeutic regimens.

描述（由申请人提供）：黑素细胞（色素产生细胞）的恶性转化导致黑色素瘤的产生。皮肤黑色素瘤是皮肤癌中最致命的形式，也是美国增长最快的癌症之一。黑色素瘤具有高度转移性，目前的治疗干预不是很有效。众所周知，黑色素瘤的形成和进展受到遗传和环境因素以及肿瘤-宿主相互作用的改变的影响。遗传学研究已经将染色体9 p21处的INK 4a/ARF鉴定为黑色素瘤易感基因座。在环境因素中，暴露于太阳辐射的紫外线（UV）光谱被认为在大多数黑色素瘤中具有偶然的作用。G偶联受体内皮素受体B（Ednr B）被认为是黑色素瘤进展标志物，体外数据表明其配体内皮素3（Edn 3）可改变黑色素瘤细胞中粘附分子的表达。本研究的目的是建立一种新的紫外线依赖性黑色素瘤小鼠模型的基础上过度激活的内皮素信号通路，以解决功能之间的关系，紫外线，遗传因素和肿瘤-宿主相互作用在黑色素瘤的发病机制。我们将使用一种诱导型转基因小鼠模型，该模型在整个发育过程中产生过量的Edn 3，导致成年小鼠皮肤中大量黑素细胞的积累，而这些黑素细胞通常不会被发现。这种情况是前体细胞增殖急剧增加的结果，这也可能是黑素细胞肿瘤形成的基础。我们将（1）评估新生儿UV暴露和内皮素信号传导途径的过度活化的组合是否足以产生转移性黑色素瘤和（2）测试ink 4a/arf在Edn 3转基因小鼠中UV诱导的黑色素瘤形成和进展中的作用。这种新的小鼠黑色素瘤模型的发展有可能有助于更好地了解这种疾病的复杂人种学，并作为一种工具，用于评估有效的预防和治疗方案。