ENVIRONMENT & GLI GENES IN NORMAL DEVELOPMENT & DISEASE

发育途径是协调行动以建立身体计划的基因网络。这些基因的破坏可能与环境暴露有关，可导致儿童和成人的严重畸形或癌症。环境科学的一个重要目标应该是减少这些不良后果。这需要了解受特定暴露影响的基因，以及这些基因或其产物改变的后果，这反过来又需要对发育过程中至关重要的途径有完整的生化理解。配体Sonic hedgehog、受体Patched和Smoothened以及转录因子GLI家族代表了这样一种途径，由于它们在间质分化的关系中具有调节功能，因此对许多器官的正常发育至关重要。环境暴露于紫外线或UVA和UCB会破坏这一途径。虽然该通路的一些基因靶点在果蝇中尚不清楚，但关键的下游靶点和上游调节因子仍有待于在哺乳动物中阐明，以及这些分子在正常发育中的作用，以便更好地了解它们在畸形发生和肿瘤发生中的作用。例如，基底细胞癌（BCC）是男性中最常见的癌症，patch突变或GLI过表达都与基底细胞癌密切相关。前列腺癌在美国是一个严重的问题，我们的初步证据表明GLI表达与人类前列腺癌有关。我们已经建立了一个独特的团队，共同研究GLI表达与人类前静态癌症。我们在西北大学建立了一个独特的合作研究团队，研究秀丽隐杆线虫、果蝇、小鼠和人类中GLI基因同源物的调控和功能。我们之前曾合作研究这些基因，目前的项目允许使用果蝇和秀丽隐杆线虫的数据来设计小鼠或人类的实验材料，这将大大增强这些努力。我们非常适合在转录，转录后和功能（蛋白质-蛋白质相互作用）水平上建立GLI基因的调控。我们工作的长期目标将是确定GLI基因的发育途径及其与环境暴露的相互作用，以便建立与下游靶点相互作用的机制。这些实验将为正常发育、出生缺陷和癌症提供重要的数据。这项工作很可能提供转录因子活性的重要通用模型，其效用将扩展到各种发育，出生缺陷和癌症。这项工作将很可能提供转录因子活性的重要通用模型，其效用将扩展到各种各样的发育和癌症问题。为了确定环境暴露对人类健康的作用，有必要清楚地了解发育基因的途径和作用的生化机制。

Developmental pathways are networks of genes which act coordinately to establish the body plan. Disruptions of these genes, which can be associated with environmental exposures, can result in serious dysmorphogenesis or cancer in both children and adults. An important goal of environmental science ought to be reduction of these poor outcomes. This will require an understanding of the genes affected by specific exposures and the consequence of alterations in these genes or their products which in turn will require a complete biochemical understanding of the pathways critical in development. The ligand Sonic hedgehog, the receptors Patched and Smoothened, and the GLI family of transcription factors represent one such pathway critical to the normal development of many organs due to their regulation functions at the nexus of mesenchymal differentiation. Environmental exposure to jervine or UVA and UCB disrupts the pathway. Although some gene targets of the pathway are not known from work in Drosophila key downstream targets and upstream regulators remain to be elucidated in mammals and the roles of these molecules established in normal development in order to better understand their role in dysmorphogenesis and neoplasia. For example, basal cell carcinoma (BCC) is the most common cancer in man and mutations in Patched or over-expression of GLI are both strongly associated with BCC. Prostatic cancer is a serious problem in the US and our preliminary evidence suggests an association of GLI expression with prostatic cancer in humans. We have established a unique team of co- investigators of GLI expression with pro-static cancer in humans. We have established a unique team of co-investigators at Northwestern University who study the regulation and function of the homologues of the GLI genes in C. elegans, Drosophila, mouse, and human. We have previously worked together to collaborate on studies of these genes and these efforts will be greatly enhanced by the current program project allowing use of data from Drosophila and C. elegans in the design of experiments in mouse, or with human material. We are uniquely suited to establish the regulation of the GLI genes at a transcriptional, post- transcriptional, and functional (protein-protein interactions) level. The long term goals of our work will be to determine pathways of development involving GLI genes and their interactions with environmental exposure, in order to establish mechanisms of interact with downstream targets. These experiments will provide data of great significance to both normal development, birth defects, and cancer. The work will very likely provide important general models of transcription factor activity whose utility will extend to a wide variety of developmental, birth defects, and cancer. The work will very likely provide important general models of transcription factor activity whose utility will extend to a wide variety of developmental and cancer problems. Clearly understanding the pathways and the biochemical mechanism of action of developmental genes will be necessary in order to determine the role of environmental exposures on human health.