Human Cell-Based Models of Primary Adipocyte Disorders

原发性脂肪细胞疾病的人体细胞模型

• 批准号: 8276036
• 负责人: Chad Albert Cowan
• 金额: $ 36.76万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8276036
• 关键词: Adipocytes; Adipose tissue; Atherosclerosis; Attention; Biological Models; Biology; Cardiovascular Diseases; Cells; Clinical; Communities; Derivation procedure; Development; Diabetes Mellitus; Disease; Disease Progression; Event; Exhibits; Face; Familial partial lipodystrophy; Fatty acid glycerol esters; Fibroblasts; Functional disorder; Generations; Genes; Genetic; Glucose Intolerance; Goals; HIV-Associated Lipodystrophy Syndrome; High Density Lipoprotein Cholesterol; Homeostasis; Human; Hypertriglyceridemia; In Vitro; Individual; Insulin Resistance; Knowledge; Lead; Light; Limb structure; Lipodystrophy; Low Prevalence; Mediating; Metabolic; Methodology; Methods; Modeling; Molecular; Morbid Obesity; Morbidity - disease rate; Mutation; Neck; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Physiological; Plasma; Play; Pluripotent Stem Cells; Premature Mortality; Prevalence; Public Health; Regulation; Research; Resources; Role; Source; Symptoms; System; Therapeutic Intervention; Triglycerides; adipocyte differentiation; base; drug development; early onset; homologous recombination; improved; in vivo; induced pluripotent stem cell; lipid biosynthesis; mutant; novel; nuclease; repaired; success

DESCRIPTION (provided by applicant): Adipose plays critical roles in the regulation of energy homeostasis and acts as an integrator of various physiological pathways. It has been increasingly recognized that adipose dysfunction causes serious public health problems that are often associated with type 2 diabetes and cardiovascular disease. The prevalence of obesity and associated metabolic complications has dramatically increased globally and has become a major cause for morbidity and premature mortality in recent years. Primary adipocyte disorders such as lipodystrophy have gained less attention than obesity, namely because of their lower prevalence. Research into acquired and genetic lipodystrophy is becoming increasingly significant as it may provide new clues to decipher the biology of primary adipocyte disorders. The hope is that by understanding the molecular mechanisms at play in these disorders it will be possible to also shed light on the mechanisms involved in obesity. Autosomal dominant partial lipodystrophy has been associated with a number of genes including LMNA and PLIN1. Mutations in the LMNA gene result in what is termed Dunnigan-type familial partial lipodystrophy syndrome type 2 (FPLD2). The major clinical feature of this disorder is fat loss in the limbs and trunk, with elevated fat storage in the neck and face. In contrast, mutations in the PLIN1 gene appear to cause a more uniform reduction of adipocytes in all depots. Due to the loss of adipose, patients exhibit metabolic dysfunction such as insulin resistance, glucose intolerance, lowered plasma high-density-lipoprotein cholesterol, and accumulation of plasma triglycerides. They often develop diabetes mellitus, hypertriglyceridemia, and early- onset atherosclerosis. Interestingly, most of these clinical symptoms are also found in individuals with morbid obesity. While the physiological consequences of LMNA and PLIN1 mutations have been described, very little about the molecular events underlying these diseases is known because of the absence of an accurate model system. Human adipose is easily obtained, however primary adipocytes are difficult to maintain in culture and are not amenable to expansion. As consequence, in vitro systems for understanding mature primary adipocyte function do not exist. In an attempt to better understand the pathophysiology of primary adipocyte dysfunctions, we propose to determine whether LMNA and PLIN1-mutant adipocytes exhibit developmental or functional differences. This will involve the derivation of induced pluripotent cells from fibroblats carrying mutations in LMNA and PLIN1 and the generation of adipocytes from LMNA and PLIN1-mutant and control iPS cells. We aim to elucidate the molecular events that lead to the development of primary adipocye disorders and seek to identify novel disease mechanisms. By examining two related but distinct forms of autosomal dominant lipodystrophy, we hope to improve our knowledge of adipose biology and dysfunction and facilitate the development of therapeutic interventions for not only lipodystrophy but also other adipose disorders such as obesity. PUBLIC HEALTH RELEVANCE: Broadly, the goal of this proposal is to determine whether LMNA and PLIN1-mutant adipocytes exhibit developmental or functional differences. This will involve the derivation of induced pluripotent cells from fibroblasts carrying mutations in LMNA and PLIN1 and the generation of adipocytes from human iPS cells. Ultimately, this strategy will improve our knowledge of adipose biology and dysfunction in primary adipocyte disorders and facilitate the development of therapeutic interventions for not only autosomal dominant partial lipodystrophy but also other adipose disorders such as obesity.

描述（由申请人提供）：脂肪在调节能量稳态中起关键作用，并充当各种生理途径的集成子。越来越多地认识到，脂肪功能障碍会引起严重的公共卫生问题，这些问题通常与2型糖尿病和心血管疾病有关。肥胖症和相关代谢并发症的流行率在全球范围内已大大提高，并且已成为近年来发病率和过早死亡的主要原因。原发性脂肪细胞疾病（如脂肪营养不良）的关注比肥胖症较少，即由于其患病率较低。对获得和遗传性脂肪营养不良的研究变得越来越重要，因为它可能提供新的线索来破译原发性脂肪细胞疾病的生物学。希望通过了解这些疾病中发挥作用的分子机制，也可以阐明肥胖中涉及的机制。常染色体显性部分脂肪营养不良与包括LMNA和PLIN1在内的许多基因有关。 LMNA基因的突变导致称为Dunnigan型家族性脂肪营养不良综合征2型（FPLD2）。这种疾病的主要临床特征是四肢和躯干中的脂肪损失，颈部和脸部脂肪储存升高。相反，PLIN1基因中的突变似乎会导致所有仓库中脂肪细胞的降低。由于脂肪的丧失，患者表现出代谢功能障碍，例如胰岛素抵抗，葡萄糖不耐症，血浆高密度脂蛋白胆固醇以及血浆甘油三酸酯的积累。他们经常患上糖尿病，高甘油三酸酯血症和早期动脉粥样硬化。有趣的是，大多数这些临床症状也出现在病态肥胖的个体中。尽管已经描述了LMNA和PLIN1突变的生理后果，但由于缺乏精确的模型系统，人们对这些疾病的分子事件的了解很少。人脂肪很容易获得，但是原发性脂肪细胞在培养中很难维持，并且不适合扩张。结果，不存在用于理解成熟原发性脂肪细胞功能的体外系统。为了更好地了解原发性脂肪细胞功能障碍的病理生理学，我们建议确定LMNA和PLIN1突变脂肪细胞是否表现出发育或功能差异。这将涉及从LMNA和PLIN1中携带突变的诱导的多能细胞衍生的诱导多能细胞，以及从LMNA和PLIN1-突变剂和对照IPS细胞的脂肪细胞产生。我们旨在阐明导致原发性脂肪疾病发展的分子事件，并试图鉴定新的疾病机制。通过研究常染色体显性脂肪营养不良的两种相关但不同的形式，我们希望提高对脂肪生物学和功能障碍的了解，并促进针对脂肪营养不良的治疗干预措施的发展，不仅是脂肪症，而且还促进了其他脂肪疾病（如肥胖）。 公共卫生相关性：从广义上讲，该提案的目的是确定LMNA和PLIN1突变脂肪细胞是否表现出发育或功能差异。这将涉及从LMNA和PLIN1中携带突变的成纤维细胞以及人IPS细胞产生脂肪细胞的诱导多能细胞。最终，该策略将提高我们对原发性脂肪细胞疾病中脂肪生物学和功能障碍的了解，并促进为常染色体主导的部分脂质营养不良的治疗干预措施的发展，以及其他其他脂肪疾病（如肥胖）。