Defining Preadipocyte Signature Genes

定义前脂肪细胞特征基因

• 批准号: 8048872
• 负责人: CYNTHIA M SMAS
• 金额: $ 23.47万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8048872
• 关键词: Defining; Preadipocyte; Signature; Genes

DESCRIPTION (provided by applicant): Obesity is at epidemic proportions in the United States and it contributes to the development of life-threatening illnesses including heart disease and type 2 diabetes. Recent studies have demonstrated a significant degree of adipocyte turnover in adult human adipose tissue, indicative of ongoing production of mature adipocytes from precursor preadipocytes. Therapies that target molecular mechanisms of adipogenesis have the potential to be effective in the treatment and prevention of obesity. The development of adipocytes from precursors present in adipose tissue is not well understood and research in this area has been limited by our inability to precisely identify this cell type. Moreover, the unique cohort of genes that define a cell as a functional preadipocyte has not been determined. As such, there remains a pressing need to develop new molecular tools to study the fat cell precursor and to identify and characterize novel pathways and molecular programs of adipogenesis. Studies with preadipocyte-expressed inhibitors of adipogenesis conducted to date indicate that this gene cohort may be a particularly rich source of regulators of the adipogenic process. This research project is designed to address gaps in our knowledge of the adipocyte lineage and preadipocyte/adipocyte biology via comprehensive approaches to identify and study genes that define functional preadipocytes. To address this we have a developed and validated a new white preadipocyte cell culture model (ScAP-23) derived from murine white adipose tissue. We will utilize this model and the highly characterized 3T3-L1 white preadipocyte model and other cell lines and analysis of preadipocyte-containing populations of WAT. Our approaches will integrate transcriptional profiling data analyzed with bioinformatics-based methodologies and functional testing of identified candidate genes and molecular pathways in preadipocytes and adipocytes. In Aim 1 we will identify novel preadipocyte-expressed inhibitors of adipogenesis and the mature adipocyte phenotype using gain of function studies conducted in preadipocytes in culture and with in vivo transplantation. In Aim 2 we will conduct genome-wide transcriptional analysis to identify genes highly enriched and selectively expressed in committed preadipocytes. Candidate preadipocyte commitment/competence genes will be tested for roles in commitment of mesenchymal precursors to the preadipocyte lineage by gain of function studies. The effect of their knockdown on preadipocyte commitment and differentiation will also be determined. We predict these studies will uncover new molecular pathways for the adipocyte lineage. In addition, our work will generate new gene expression datasets highly useful to the research community and will form an important foundation for the development of new molecular tools to study preadipocytes. PUBLIC HEALTH RELEVANCE: By determining the molecular processes underlying the formation and function of adipose tissue we can better define therapies and treatments for obesity. While there is considerable information on the genes which function in adipocytes, those which that are important for the cell type from which mature adipocytes arise, termed preadipocytes, remain largely unexplored. By better defining these genes and their functions we aim to uncover unique ways to study the development of adipose tissue and control the process of conversion of preadipocytes to adipocytes that will ultimately lead to better understanding and treatment of obesity.

描述（由申请人提供）：肥胖在美国是流行病，它有助于发展危及生命的疾病，包括心脏病和2型糖尿病。最近的研究表明，成人脂肪组织中脂肪细胞的更新程度很高，这表明前体脂肪细胞不断产生成熟脂肪细胞。靶向脂肪形成的分子机制的疗法具有有效治疗和预防肥胖的潜力。从脂肪组织中存在的前体细胞发育成脂肪细胞还没有很好地理解，并且由于我们不能精确地鉴定这种细胞类型，因此该领域的研究受到限制。此外，将细胞定义为功能性前脂肪细胞的独特基因组尚未确定。因此，仍然迫切需要开发新的分子工具来研究脂肪细胞前体并鉴定和表征脂肪形成的新途径和分子程序。迄今为止，对前脂肪细胞表达的脂肪形成抑制剂的研究表明，该基因组可能是脂肪形成过程调节剂的特别丰富的来源。该研究项目旨在通过全面的方法来识别和研究定义功能性前脂肪细胞的基因，以解决我们对脂肪细胞谱系和前脂肪细胞/脂肪细胞生物学知识的差距。为了解决这一问题，我们开发并验证了一种新的来源于鼠白色脂肪组织的白色前脂肪细胞培养模型（ScAP-23）。我们将利用该模型和高度表征的3 T3-L1白色前脂肪细胞模型和其他细胞系，并分析含前脂肪细胞的WAT群体。我们的方法将整合基于生物信息学的方法分析的转录谱数据，并对前脂肪细胞和脂肪细胞中已确定的候选基因和分子通路进行功能测试。在目标1中，我们将通过在培养的前脂肪细胞和体内移植中进行的功能获得研究来鉴定新的前脂肪细胞表达的脂肪生成抑制剂和成熟脂肪细胞表型。在目标2中，我们将进行全基因组转录分析，以确定基因高度富集和选择性表达的定向前脂肪细胞。候选前脂肪细胞定型/能力基因将通过功能获得研究来测试在间充质前体向前脂肪细胞谱系定型中的作用。还将确定它们的敲除对前脂肪细胞定型和分化的影响。我们预测这些研究将揭示脂肪细胞谱系的新分子途径。此外，我们的工作将产生对研究界非常有用的新基因表达数据集，并将为开发研究前脂肪细胞的新分子工具奠定重要基础。 公共卫生关系：通过确定脂肪组织形成和功能的分子过程，我们可以更好地确定肥胖症的治疗方法。虽然有相当多的信息在脂肪细胞中发挥作用的基因，那些是重要的细胞类型的成熟脂肪细胞的出现，称为前脂肪细胞，仍然在很大程度上未被探索。通过更好地定义这些基因及其功能，我们的目标是揭示研究脂肪组织发育的独特方法，并控制前脂肪细胞转化为脂肪细胞的过程，最终导致更好地理解和治疗肥胖。