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）：脂肪在能量稳态调节中起关键作用，并作为各种生理途径的整合剂。人们越来越认识到，脂肪功能障碍会导致严重的公共卫生问题，这些问题往往与2型糖尿病和心血管疾病有关。近年来，肥胖症和相关代谢并发症的患病率在全球范围内急剧增加，并已成为发病率和过早死亡率的主要原因。原发性脂肪细胞疾病如脂肪营养不良获得的关注少于肥胖症，即因为其患病率较低。对获得性和遗传性脂肪代谢障碍的研究正变得越来越重要，因为它可能为破译原发性脂肪细胞疾病的生物学提供新的线索。希望通过了解在这些疾病中起作用的分子机制，也有可能揭示肥胖的机制。常染色体显性部分脂肪营养不良与许多基因相关，包括LMNA和PLIN 1。LMNA基因突变导致Dunnigan型家族性部分脂肪营养不良综合征2型（FPLD 2）。这种疾病的主要临床特征是四肢和躯干的脂肪减少，颈部和面部的脂肪储存增加。相比之下，PLIN 1基因的突变似乎导致所有贮库中脂肪细胞的更均匀减少。由于脂肪的损失，患者表现出代谢功能障碍，如胰岛素抵抗、葡萄糖耐受不良、血浆高密度脂蛋白胆固醇降低和血浆甘油三酯蓄积。他们经常发展为糖尿病、高血糖和早发性动脉粥样硬化.有趣的是，这些临床症状中的大多数也在病态肥胖的个体中发现。虽然已经描述了LMNA和PLIN 1突变的生理后果，但由于缺乏准确的模型系统，对这些疾病的分子事件知之甚少。人类脂肪很容易获得，但原代脂肪细胞难以在培养中维持并且不适合扩增。因此，用于理解成熟的原代脂肪细胞功能的体外系统不存在。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PLIN 1突变脂肪细胞是否表现出发育或功能差异。这将涉及从携带LMNA和PLIN 1突变的成纤维细胞衍生诱导多能细胞，以及从LMNA和PLIN 1突变体和对照iPS细胞产生脂肪细胞。我们的目的是阐明导致原发性脂肪细胞疾病发展的分子事件，并寻求确定新的疾病机制。通过研究两种相关但不同形式的常染色体显性脂肪营养不良，我们希望提高我们的知识脂肪生物学和功能障碍，促进治疗干预的发展，不仅脂肪营养不良，但也其他脂肪疾病，如肥胖。 公共卫生相关性：概括地说，该提案的目标是确定LMNA和PLIN 1突变脂肪细胞是否表现出发育或功能差异。这将涉及从携带LMNA和PLIN 1突变的成纤维细胞衍生诱导多能细胞，以及从人iPS细胞产生脂肪细胞。最终，这一策略将提高我们对脂肪生物学和原发性脂肪细胞疾病功能障碍的认识，并促进不仅常染色体显性部分脂肪营养不良而且其他脂肪疾病（如肥胖）的治疗干预措施的发展。