ENVIRONMENT & GLI GENES IN NORMAL DEVELOPMENT & DISEASE

环境

• 批准号: 6656899
• 负责人: Philip M Iannaccone
• 金额: $ 57.65万
• 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/6656899
• 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.

发育途径是基因的网络，它们协调行动以建立身体计划。这些基因的破坏可能与环境暴露有关，可能导致儿童和成人严重的畸形或癌症。环境科学的一个重要目标应该是减少这些不良后果。这将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关键途径的完整生物化学理解。配体Sonic hedgehog、受体Patched和Smoothened以及转录因子的GLI家族代表了一种这样的途径，该途径对于许多器官的正常发育至关重要，这是由于它们在间充质分化的关系中的调节功能。环境暴露于jervine或UVA和UCB会破坏该途径。虽然一些基因靶点的途径是不知道从工作中的果蝇关键下游目标和上游调控仍有待阐明在哺乳动物和这些分子的作用，建立在正常发育，以更好地了解他们的作用，在畸形和肿瘤。例如，基底细胞癌（BCC）是人类中最常见的癌症，并且GLI的斑片状或过表达的突变都与BCC强烈相关。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相关。我们已经建立了一个独特的团队，共同研究GLI表达与人类前列腺癌。我们在西北大学建立了一支独特的联合研究人员团队，研究C中GLI基因同源物的调节和功能。线虫、果蝇、小鼠和人类。我们以前曾在这些基因的研究上合作过，目前的项目允许使用果蝇和C.在小鼠实验设计中，或与人类材料。我们是唯一适合于建立GLI基因在转录，转录后，和功能（蛋白质-蛋白质相互作用）水平的调控。我们工作的长期目标将是确定涉及GLI基因的发育途径及其与环境暴露的相互作用，以建立与下游靶点相互作用的机制。这些实验将提供对正常发育、出生缺陷和癌症具有重要意义的数据。这项工作将很可能提供重要的转录因子活性的一般模型，其效用将扩展到各种各样的发育，出生缺陷和癌症。这项工作将很可能提供重要的通用模型的转录因子活动，其效用将扩展到各种各样的发展和癌症问题。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作用途径和生化机制。