Mechanism of Promotion of Adipogenesis by Adenovirus-36

腺病毒36促进脂肪生成的机制

• 批准号: 6846866
• 负责人: NIKHIL V DHURANDHAR
• 金额: $ 7.32万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2005-05-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846866
• 关键词: 3T3 cells; Adenoviridae; adipocytes; cell differentiation; gene expression; genetic transcription; obesity; polymerase chain reaction; transfection; virus genetics; virus infection mechanism

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.

描述（由申请人提供）：肥胖是一种具有多种原因的慢性疾病，在美国已达到流行病的比例。识别和了解所涉及的各种病因可能有助于设计针对适当原因的更好治疗方法。据报道，五种病毒在动物模型中引起肥胖，病毒感染可能在某些形式的人类肥胖中起病因学作用。我们最近报道了腺病毒36型（Ad-36），这是第一种在实验动物（包括非人灵长类动物）中增加肥胖的人类病毒，与人类肥胖有关。我们用3 T3-L1细胞（啮齿动物前脂肪细胞系）和人前脂肪细胞进行的体外实验显示，Ad-36诱导脂肪细胞分化上调，并调节脂肪细胞分化途径中的几个基因的表达。我们的中心假设是，脂肪细胞分化的上调有助于显着的Ad-36的成脂作用。本研究的目的是探讨脂肪细胞与Ad-36之间的分子相互作用，为阐明Ad-36促进脂肪细胞形成的机制提供基础。初步数据表明，只有一个子集的病毒基因表达的Ad-36感染的前脂肪细胞。在具体目标1中，我们将开始通过鉴定感染的前脂肪细胞分化过程中表达的Ad-36转录单位。从这些候选者中，特异性目标2将鉴定增强前脂肪细胞分化的病毒转录单位。接下来，特异性Aim 3将确定由特异性Aim 2以及Ad-36病毒中鉴定的候选转录单位引起的细胞基因表达的分化相关变化。Ad-2（一种非脂肪形成性人腺病毒）将用作阴性对照。此外，将测试发现增强3 T3-L1细胞分化的基因对人前脂肪细胞分化的影响。鉴定相互作用的病毒和细胞基因将有助于将来阐明脂肪细胞分化的新信号传导控制和Ad-36诱导的肥胖的分子途径。对Ad-36诱导肥胖的机制的理解将有助于确定Ad-36感染在人类肥胖中的贡献。我们相信，确定病毒感染在人类肥胖中的作用可能会影响这种类型的肥胖的治疗，管理和可能的预防。