Human Cell-Based Models of Primary Adipocyte Disorders
原发性脂肪细胞疾病的人体细胞模型
基本信息
- 批准号:8442851
- 负责人:
- 金额:$ 35.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdipocytesAdipose tissueAtherosclerosisAttentionBiological ModelsBiologyCardiovascular DiseasesCellsClinicalCommunitiesDerivation procedureDevelopmentDiabetes MellitusDiseaseDisease ProgressionEventExhibitsFaceFamilial partial lipodystrophyFatty acid glycerol estersFibroblastsFunctional disorderGenerationsGenesGeneticGlucose IntoleranceGoalsHIV-Associated Lipodystrophy SyndromeHigh Density Lipoprotein CholesterolHomeostasisHumanHypertriglyceridemiaIn VitroIndividualInsulin ResistanceKnowledgeLeadLightLimb structureLipodystrophyLow PrevalenceMediatingMetabolicMethodologyMethodsModelingMolecularMorbid ObesityMorbidity - disease rateMutationNeckNon-Insulin-Dependent Diabetes MellitusObesityPathway interactionsPatientsPhysiologicalPlasmaPlayPluripotent Stem CellsPremature MortalityPrevalencePublic HealthRegulationResearchResourcesRoleSourceSymptomsSystemTherapeutic InterventionTriglyceridesadipocyte differentiationbasedrug developmentearly onsethomologous recombinationimprovedin vivoinduced pluripotent stem celllipid biosynthesismutantnovelnucleaserepairedsuccess
项目摘要
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.
描述(申请人提供):脂肪在能量平衡的调节中起关键作用,并作为各种生理途径的整合者。人们越来越认识到,脂肪功能障碍会导致严重的公共健康问题,而这些问题往往与2型糖尿病和心血管疾病有关。肥胖及其相关代谢并发症的流行在全球范围内急剧增加,并已成为近年来发病率和过早死亡的主要原因。与肥胖相比,脂肪营养不良等原发性脂肪细胞疾病受到的关注较少,这是因为它们的患病率较低。对获得性和遗传性脂肪营养不良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,也有可能阐明肥胖涉及的机制。常染色体显性遗传性部分性脂肪营养不良与LMNA和PLIN1等基因相关。LMNA基因的突变导致所谓的Dunnigan型家族性部分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的脂肪减少,颈部和面部的脂肪储存增加。相比之下,PLIN1基因的突变似乎会导致所有脂肪细胞更加均匀地减少。由于脂肪丢失,患者出现代谢功能障碍,如胰岛素抵抗、糖耐量减低、血浆高密度脂蛋白胆固醇降低和血浆甘油三酯积聚。他们经常患上糖尿病、高甘油三酯血症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出现在病态肥胖症患者身上。虽然LMNA和PLIN1突变的生理后果已经被描述,但由于缺乏准确的模型系统,对这些疾病背后的分子事件知之甚少。人的脂肪很容易获得,但原代脂肪细胞在培养中很难保持,不能扩增。因此,目前尚不存在了解成熟原代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机制,我们建议确定LMNA和PLIN1突变的脂肪细胞是否表现出发育或功能上的差异。这将包括从携带LMNA和PLIN1突变的成纤维细胞中获得诱导的多能细胞,以及从LMNA和PLIN1突变的iPS细胞中产生脂肪细胞。我们的目标是阐明导致原发性脂肪细胞疾病发展的分子事件,并寻求识别新的疾病机制。通过研究两种相关但不同的常染色体显性脂肪营养不良症,我们希望提高我们对脂肪生物学和功能障碍的知识,并促进不仅针对脂肪营养不良而且针对肥胖等其他脂肪疾病的治疗干预措施的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Chad Albert Cowan其他文献
Chad Albert Cowan的其他文献
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{{ truncateString('Chad Albert Cowan', 18)}}的其他基金
A National iPS Cell Network with Deep Phenotyping for Translational Research
具有深度表型分析功能的国家 iPS 细胞网络,用于转化研究
- 批准号:
9354528 - 财政年份:2016
- 资助金额:
$ 35.47万 - 项目类别:
A National iPS Cell Network with Deep Phenotyping for Translational Research
具有深度表型分析功能的国家 iPS 细胞网络,用于转化研究
- 批准号:
9214660 - 财政年份:2016
- 资助金额:
$ 35.47万 - 项目类别:
A National iPS Cell Network with Deep Phenotyping for Translational Research
具有深度表型分析功能的国家 iPS 细胞网络,用于转化研究
- 批准号:
9752329 - 财政年份:2016
- 资助金额:
$ 35.47万 - 项目类别:
Systematic cell-based functional screening for LDL and triglyceride genes
基于细胞的系统性低密度脂蛋白和甘油三酯基因功能筛查
- 批准号:
9322539 - 财政年份:2014
- 资助金额:
$ 35.47万 - 项目类别:
Systematic cell-based functional screening for LDL and triglyceride genes
基于细胞的系统性低密度脂蛋白和甘油三酯基因功能筛查
- 批准号:
8758133 - 财政年份:2014
- 资助金额:
$ 35.47万 - 项目类别:
Systematic cell-based functional screening for LDL and triglyceride genes
基于细胞的系统性低密度脂蛋白和甘油三酯基因功能筛查
- 批准号:
8908038 - 财政年份:2014
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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:
8840225 - 财政年份:2012
- 资助金额:
$ 35.47万 - 项目类别:
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:
8662769 - 财政年份:2012
- 资助金额:
$ 35.47万 - 项目类别:
Isogenic Human Pluripotent Stem Cell-Based Models of Human Disease Mutations
基于同基因人类多能干细胞的人类疾病突变模型
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8723820 - 财政年份:2012
- 资助金额:
$ 35.47万 - 项目类别:
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 - 财政年份:2012
- 资助金额:
$ 35.47万 - 项目类别:
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