Spatial changes in gene organization during adipogenesis

描述（由申请人提供）：肥胖和与肥胖相关的健康并发症，包括糖尿病，影响美国相当大比例的人口，预测表明，肥胖和超重的人数在未来将继续上升。由于肥胖症和相关并发症造成的身体和心理社会问题，再加上相关的生产力损失，保健费用惊人。虽然有必要改善肥胖和超重人群的生活方式改变策略，但必须继续进行基础研究，以了解调节体重增加的生理过程。人们已经付出了相当大的努力来鉴定在脂肪组织形成过程中被打开的基因，研究它们的功能，并确定这些基因的表达被调节的机制。有助于脂肪形成的分子的鉴定将可能继续导致以可用于治疗肥胖症和肥胖症相关疾病的方式调节脂肪形成的策略的开发。然而，最近开发的方法导致了一个新兴的研究领域，它不仅关注单个基因的调控，而且允许分析任何感兴趣的生物过程中涉及的基因的三维结构。我们的初步研究表明，在脂肪形成分化开始后不久，在脂肪形成过程中表达的基因在三维空间中彼此物理相关，尽管它们位于不同的染色体上，并且在分化前没有接触。这种基因关联或聚类是脂肪形成过程中发生的一种以前未被表征的事件。PI和co-PI开发了导致这一发现的方法，现在寻求进一步表征脂肪形成过程中的基因簇，研究其功能相关性，并确定促成或需要其发生的因素。我们设想，最终我们的研究和其他性质相似的研究将导致控制基因表达和细胞分化的新过程的定义，以及介导这些过程的先前未知分子的鉴定。此外，我们认为这些分子可能代表了一类全新的药物设计和筛选靶点。肥胖和与肥胖相关的健康并发症，包括糖尿病，影响了美国很大一部分人口。虽然有必要改善肥胖和超重人群生活方式的改变，但必须继续进行基础研究，以了解调节体重增加的生理过程。我们已经发现，在脂肪细胞形成过程中表达的基因在三维空间中彼此物理关联，尽管它们位于不同的染色体上，并且在脂肪细胞分化之前没有接触。这种基因关联或聚类是脂肪形成过程中发生的一种以前未被表征的事件。基因聚类的进一步表征可能导致控制基因表达和细胞分化的新过程的定义，以及介导这些过程的先前未知分子的鉴定。这些分子可能代表了未来治疗的全新靶点。

DESCRIPTION (provided by applicant): Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the U.S., and projections indicate that the number of obese and overweight individuals will continue to rise in the future. The costs of health care due to the physical and psycho-social problems caused by obesity and related complications, coupled with the associated loss of productivity, are staggering. While it is necessary to improve strategies that will result in lifestyle changes among the obese and overweight population, basic research toward understanding the physiological processes regulating weight gain must be continued. Considerable effort has been placed on identifying genes that are turned on during the formation of adipose tissue, investigating their function, and determining the mechanisms by which the expression of these genes are regulated. Identification of molecules that contribute to adipogenesis will likely continue to lead to the development of strategies to modulate adipogenesis in a manner that is useful for the treatment of obesity and obesity related disease. However, recently developed methodologies have led to an emerging field of research that does not simply focus on the regulation of individual genes but instead permits analysis of the three-dimensional structure of genes involved in any biological process of interest. Our initial studies reveal that shortly after the onset of adipogenic differentiation, genes that will be expressed during adipogenesis are physically associated with each other in three-dimensional space despite the fact that they are located on different chromosomes and were not in contact prior to differentiation. This gene association, or clustering, is a previously uncharacterized event that occurs during adipogenesis. The PI and the co-PI, who developed the methodologies that led to this discovery, now seek to further characterize gene clustering during adipogenesis, investigate its functional relevance, and identify factors that contribute to or are required for its occurrence. We envision that ultimately our studies and others that are similar in nature will result in the definition of new processes controlling gene expression and cellular differentiation and in the identification of previously unknown molecules that mediate these processes. Furthermore, we propose that such molecules may represent an entirely new class of targets for drug design and screening. Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the U.S. While it is necessary to improve strategies that will result in lifestyle changes among the obese and overweight population, basic research toward understanding the physiological processes regulating weight gain must be continued. We have discovered that genes that will be expressed during the formation of fat cells are physically associated with each other in three-dimensional space despite the fact that they are located on different chromosomes and were not in contact prior to fat cell differentiation. This gene association, or clustering, is a previously uncharacterized event that occurs during adipogenesis. Further characterization of gene clustering may result in the definition of new processes controlling gene expression and cellular differentiation and in the identification of previously unknown molecules that mediate these processes. Such molecules may represent an entirely new class of targets for future therapies.