Mechanism of Promotion of Adipogenesis by Adenovirus-36

描述(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的程度。由于相对缺乏有效的治疗方法，这个问题变得更加复杂。识别和了解涉及的各种病因可能有助于针对适当的病因设计更好的治疗方法。据报道，有五种病毒在动物模型中导致肥胖，病毒感染可能在某些形式的人类肥胖中起到病因学作用。我们最近报道了36型腺病毒(Ad-36)，这是第一种人类病毒，可以增加包括非人类灵长类动物在内的实验动物的肥胖，并与人类肥胖有关。我们用3T3-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表明，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，上调脂肪细胞分化对Ad-36的成脂作用有重要贡献。本研究的目的是确定脂肪细胞与Ad-36之间的分子相互作用，为阐明促进脂肪生成的机制提供依据。初步数据表明，只有一部分病毒基因在Ad-36感染的前脂肪细胞中表达。在特定的目标1中，我们将首先鉴定在感染的前脂肪细胞分化过程中表达的Ad-36转录单位。从这些候选基因中，特定目标2将识别促进前脂肪细胞分化的病毒转录单位(S)。接下来，特定目标3将确定特定目标2中确定的候选转录单位以及Ad-36病毒所引起的细胞基因表达的分化相关变化。AD-2，一种非成脂人腺病毒，将作为阴性对照。此外，还将测试被发现促进3T3-L1细胞分化的基因对人类前脂肪细胞分化的影响。确定病毒和细胞相互作用的基因将有助于阐明脂肪细胞分化的新的信号调控和Ad-36诱导肥胖的分子途径(S)。了解Ad-36诱导肥胖的机制将有助于确定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此类肥胖症的治疗、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.