ENVIRONMENT & GLI GENES IN NORMAL DEVELOPMENT & DISEASE

环境

• 批准号: 6158349
• 负责人: Philip M Iannaccone
• 金额: $ 54.02万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6158349
• 关键词: developmental genetics; environmental toxicology; transcription factor

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.

发育途径是基因网络，它们协同起作用以建立身体计划。这些基因的破坏可能与环境暴露有关，可能会导致儿童和成人的严重畸形发生或癌症。环境科学的一个重要目标应该是减少这些不良结果。这将需要了解受特定暴露影响的基因以及这些基因或其产品改变的后果，而这些基因或其产物的变化反过来又需要对开发至关重要的途径有完全的生化理解。配体声波刺猬，被修补和平滑的受体，转录因子的GLI家族代表了一种对许多器官正常发育至关重要的途径，这是由于其调节功能在间充质分化的Nexus上的调节功能。环境暴露于Jervine或UVA和UCB会破坏该路径。尽管该途径的某些基因靶标在果蝇关键的下游靶标的工作中尚不清楚，并且上游调节剂在哺乳动物中仍有尚待阐明，并且在正常发育中确立的这些分子的作用在正常发育中的作用，以便更好地了解它们在畸形生成和Neoplasia中的作用。例如，基底细胞癌（BCC）是人类中最常见的癌症，而GLI修补或过表达的突变都与BCC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的关联。我们已经建立了一个独特的GLI表达合作者团队，该团队在人类中与静态癌症相关。我们已经在西北大学建立了一个独特的共同投资者团队，他们研究了秀丽隐杆线虫，果蝇，小鼠和人类Gli基因同源物的调节和功能。我们以前曾共同合作研究这些基因的研究，当前的计划项目将大大提高这些努力，从而允许使用果蝇和秀丽隐杆线虫的数据来设计小鼠的实验或人类材料。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基因的调节。我们工作的长期目标是确定涉及GLI基因的发展途径及其与环境暴露的相互作用，以建立与下游目标相互作用的机制。这些实验将为正常发育，先天缺陷和癌症提供重要意义的数据。这项工作很可能会提供转录因子活动的重要一般模型，这些模型将扩展到各种发育，出生缺陷和癌症。这项工作很可能会提供转录因子活动的重要一般模型，这些模型将扩展到各种发育和癌症问题。清楚地了解发展基因作用的途径和生化机理，以确定环境暴露对人类健康的作用。