Mechanism of Promotion of Adipogenesis by Adenovirus-36

描述（由申请人提供）：肥胖是一种由多种原因引起的慢性疾病，在美国已经达到流行病的程度。由于相对缺乏有效的治疗方法，问题变得更加复杂。识别和了解所涉及的各种病因可能有助于设计针对适当病因的更好的治疗方法。据报道，在动物模型中有五种病毒引起肥胖，病毒感染可能在某些形式的人类肥胖中起病因学作用。我们最近报道了36型腺病毒（Ad-36），这是第一种在实验动物（包括非人类灵长类动物）中增加肥胖的人类病毒，并与人类肥胖有关。我们对3T3-L1细胞（啮齿动物前脂肪细胞系）和人前脂肪细胞的体外实验表明，ad -36诱导脂肪细胞分化上调，并调节脂肪细胞分化通路中多个基因的表达。我们的中心假设是脂肪细胞分化的上调对Ad-36的成脂作用有重要贡献。本课题的目的是明确脂肪细胞与Ad-36之间的分子相互作用，为阐明Ad-36促进脂肪形成的机制提供基础。初步数据表明，只有一小部分病毒基因在Ad-36感染的前脂肪细胞中表达。在特异性目标1中，我们将从鉴定感染前脂肪细胞分化过程中表达的Ad-36转录单位开始。从这些候选细胞中，Specific Aim 2将识别增强前脂肪细胞分化的病毒转录单位。接下来，特异性Aim 3将确定在特异性Aim 2和Ad-36病毒中鉴定的候选转录单元所引起的细胞基因表达的分化相关变化。非致脂性人腺病毒Ad-2作为阴性对照。此外，研究人员还将测试能够促进3T3-L1细胞分化的基因对人类前脂肪细胞分化的影响。识别相互作用的病毒和细胞基因将有助于未来阐明脂肪细胞分化的新信号控制和Ad-36诱导肥胖的分子途径。对Ad-36诱导肥胖机制的理解将有助于确定Ad-36感染在人类肥胖中的作用。我们认为，确定病毒感染在人类肥胖中的作用可能会影响这类肥胖的治疗、管理和可能的预防。

DESCRIPTION (provided by applicant): Obesity is a chronic condition with multiple causes, which has reached epidemic proportions in the U.S. The problem is compounded by a relative lack of effective treatments. Identifying and understanding various etiological factors involved may help in designing better treatments directed at the appropriate causes. Five viruses are reported to cause obesity in animal models, and viral infection may play an etiological role in some forms of human obesity. We recently reported adenovirus type-36 (Ad-36), the first human virus that increases adiposity in experimental animals including non-human primates and is associated with human obesity. Our in-vitro experiments with 3T3-L1 cells (rodent preadipocytes cell line) and human preadipocytes show Ad-36-induces up-regulation of fat cell differentiation and modulates the expression of several genes in fat cell differentiation pathway. Our central hypothesis is that up-regulation of fat cell differentiation contributes significantly to the adipogenic effect of Ad-36. The objective of this proposal is to identify the molecular interactions between fat cells and Ad-36, which will provide the basis to elucidate the mechanism of promotion of adipogenesis. Preliminary data suggested that the only a subset of viral genes are expressed in Ad-36 infected preadipocytes. In Specific Aim 1, we will begin by identifying the Ad-36 transcription units expressed during differentiation of infected preadipocytes. From these candidates, the Specific Aim 2 will identify the viral transcription unit(s) that enhance preadipocyte differentiation. Next, the Specific Aim 3 will determine the differentiation-associated changes in cellular gene expression prompted by the candidate transcription unit identified in Specific Aim 2 as well as Ad-36 virus. Ad-2, a non-adipogenic human adenovirus will be used as a negative control. Also, genes found to enhance the differentiation of 3T3-L1 cells will be tested for their effect on differentiation of human preadipocytes. Identifying the interacting viral and cellular genes will help in future for elucidating novel signaling controls of fat cell differentiation and molecular pathway(s) for Ad-36 induced adiposity. Such an understanding of the mechanism of Ad-36 induced adiposity will help in determining the contribution of Ad-36 infections in human obesity. We believe that determining the role of viral infections in human obesity may influence the treatment, management, and possible prevention of such type of obesity.