Defining Preadipocyte Signature Genes

定义前脂肪细胞特征基因

基本信息

批准号：
8144760
负责人：
CYNTHIA M SMAS
金额：
$ 18.85万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144760
关键词：
Address Adipocytes Adipose tissue Adult Affect Area Automobile Driving Bioinformatics Biological Assay Candidate Disease Gene Cell Count Cell Culture Techniques Cell Line Cell Separation Cell physiology Cells Child Chronic Commit Communities Comorbidity Competence Coupled Data Analyses Data Set Development Down-Regulation Epidemic Fibroblasts Foundations Gene Expression Genes Goals Health Heart Diseases Human In Vitro Inflammatory Knowledge Lead Life Life Cycle Stages Maintenance Malignant Neoplasms Membrane Proteins Mesenchymal Mesenchymal Stem Cells Methodology Modeling Molecular Molecular Profiling Molecular Target Mus Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Phenotype Pilot Projects Population Process Production Research Research Personnel Research Project Grants Role Screening procedure Signal Transduction Source Systems Biology Testing Tissues Transplantation United States Work adipocyte biology adipocyte differentiation base cell type cohort cost design early onset fight against gain of function genome-wide in vitro Model in vivo inhibitor/antagonist lipid biosynthesis loss of function middle age novel novel strategies obesity prevention obesity treatment programs promoter public health relevance selective expression tool tool development

项目摘要

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）：肥胖症在美国处于流行比例，这有助于危及生命的疾病，包括心脏病和2型糖尿病。最近的研究表明，成人人类脂肪组织的脂肪细胞更新很大，这表明持续产生来自前体前脂肪细胞成熟的脂肪细胞。靶向脂肪生成的分子机制的疗法有可能有效地治疗和预防肥胖症。脂肪组织中存在的前体的脂肪细胞的发展尚不清楚，并且在该领域的研究受到了我们无法精确识别这种细胞类型的限制。此外，尚未确定将细胞定义为功能性前细胞的独特基因队列。因此，仍然需要开发新的分子工具来研究脂肪细胞前体并识别和表征脂肪生成的新途径和分子程序。迄今为止，对脂肪生成前表达的脂肪生成抑制剂的研究表明，该基因组可能是掺杂过程的调节剂的特别丰富来源。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脂肪细胞/脂肪细胞生物学的差距。为了解决这个问题，我们有一个开发并验证了一种来自鼠白脂肪组织的新的白色前脂肪细胞培养模型（SCAP-23）。我们将利用此模型，并具有高度特征的3T3-L1白色前脂肪细胞模型和其他细胞系，并分析含有preadipocyte的含有wat的前细胞。我们的方法将与基于生物信息学方法的方法和鉴定候选基因的功能测试以及在前脂肪细胞和脂肪细胞中的分子途径进行分析的转录分析数据。在AIM 1中，我们将使用在培养前和体内移植中进行的功能研究获得的新型前表达脂肪生成前表达的抑制剂和成熟的脂肪细胞表型。在AIM 2中，我们将进行全基因组的转录分析，以鉴定在认可的前脂肪细胞中高度富集并选择性地表达的基因。候选前脂肪细胞的承诺/能力基因将通过功能研究的获取来测试在间充质前体对前膜细胞谱系的承诺中的作用。他们的敲低对前脂肪细胞承诺和分化的影响也将得到确定。我们预测这些研究将发现脂肪细胞谱系的新分子途径。此外，我们的工作将生成对研究社区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构成重要的基础。公共卫生相关性：通过确定脂肪组织形成和功能的分子过程，我们可以更好地定义肥胖症的疗法和治疗方法。尽管有关在脂肪细胞中起作用的基因的大量信息，但对于成熟的脂肪细胞出现的细胞类型至关重要的基因，称为脂肪细胞，称为前脂肪细胞，在很大程度上尚未探索。通过更好地定义这些基因及其功能，我们旨在发现研究脂肪组织发展的独特方法，并控制前脂肪细胞转化为脂肪细胞的过程，从而最终导致更好地理解和治疗肥胖。