Genetic and Metabolic Basis of Familial Lipodystrophies

家族性脂肪营养不良的遗传和代谢基础

基本信息

批准号：
9237269
负责人：
Abhimanyu Garg
金额：
$ 55.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-16 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237269
关键词：
1q21 AKT2 gene Acanthosis Nigricans Acyltransferase Adipocytes Adipose tissue Affect Body fat Candidate Disease Gene Cell Death Cessation of life Characteristics Chromosomes Clinical Contracture DNA Fragmentation Defect Development Diabetes Mellitus Disease Dyslipidemias Dysplasia Etiology Familial generalized lipodystrophy Familial partial lipodystrophy Family Family member Fatty Liver Genes Genetic Genomics Goals Grant HIV-Associated Lipodystrophy Syndrome Health Hernia Homologous Gene Hypertriglyceridemia Insulin Resistance Joints Knowledge Laboratories Lamin Type A Lead Light Link Lipodystrophy Mandible Mendelian disorder Mental Depression Metabolic Metalloproteases Modernization Molecular Morbidity - disease rate Mus Muscular Atrophy Mutation Neonatal Obesity Oncogenes PPAR gamma Panniculitis Paris, France Pathway interactions Patients Phenotype Phosphatidylinositols Phosphotransferases Polymerase Population Process Proto-Oncogene Proteins c-akt Reporting Rieger syndrome Role Syndrome Technology Teething Therapeutic Intervention Thymoma Transcript Variant Wiedemann-Rautenstrauch syndrome Work Zinc adipocyte biology adipocyte differentiation autoinflammatory caveolin 1 clinical phenotype deafness disease-causing mutation early onset exome sequencing factor A genetic linkage analysis genetic pedigree genetic variant genome-wide linkage in vitro Assay inorganic phosphate insight metabolic abnormality assessment microcytic anemia multicatalytic endopeptidase complex new therapeutic target next generation novel novel therapeutics perilipin positional cloning proband public health relevance release factor

项目摘要

DESCRIPTION (provided by applicant): Obesity remains a major health problem in US and causes metabolic complications such as diabetes, dyslipidemia and insulin resistance. Similar complications also occur in patients with familial lipodystrophies characterized by partial (familil partial lipodystrophy, FPL) or almost complete (congenital generalized lipodystrophy, CGL) lack of body fat. In the last few years, several genes for CGL (AGPAT2, BSCL2, CAV1 and PTRF); FPL (LMNA, PPARG, AKT2, CIDEC and PLIN1); mandibuloacral dysplasia (MAD; LMNA and ZMPSTE24); autoinflammatory (PSMB8); SHORT syndrome (short stature, hyperextensibility/hernias, ocular depression, Rieger anomaly and teething delay; PIK3R1); and MDP (mandibular hypoplasia, deafness and progeroid features) syndrome (POLD1) associated lipodystrophies have been identified. However, affected subjects from approximately 200 pedigrees with CGL, MAD and especially FPL lack mutations in these genes suggesting additional loci. Furthermore, the genetic basis of many extremely rare varieties of lipodystrophies associated with SHORT and neonatal progeroid syndromes remains unknown. Thus, the first aim of this proposal is to identify additional gene(s) involved in adipocyte biolog, development and differentiation that cause lipodystrophies and to determine their function in adipocyte biology. We will use state-of-the-art whole exome sequencing to identify the molecular defects in these families. The second aim is to ascertain relationships between molecular defects in lipodystrophy genes with metabolic derangements using well-phenotyped probands, families, and populations. These studies will unravel molecular mechanisms involved in causation of lipodystrophy, and insulin resistance and its associated morbidities. This new knowledge may provide targets for developing novel drugs for treating diabetes, dyslipidemias and hepatic steatosis.

描述（由适用提供）：肥胖仍然是美国的主要健康问题，并导致代谢并发症，例如糖尿病，血脂异常和胰岛素抵抗。患有脂肪营养不良的患者也发生了类似的并发症，其特征是部分（家族部分脂肪营养不良，FPL）或几乎完整（先天普遍的脂肪营养不良，CGL）缺乏体内脂肪。在过去的几年中，CGL的几个基因（AGPAT2，BSCL2，CAV1和PTRF）； FPL（LMNA，PPARG，AKT2，CIDEC和PLIN1）;下腹发育不良（MAD; LMNA和ZMPSTE24）;自动炎症（PSMB8）;短综合征（身材矮小，过度伸缩/疝气，眼部抑郁，Rieger异常和出牙延迟； Pik3r1）；已经鉴定出了MDP（下颌骨发育不全，耳聋和后代特征）综合征（POLD1）相关的脂肪营养不良。然而，在这些基因中，大约200个具有CGL，MAD，尤其是FPL的受试者缺乏突变表明额外的基因座。此外，与短和新生儿后代综合征相关的许多极为罕见的脂肪营养不良变化的遗传基础仍然未知。这是该提案的第一个目的是确定引起脂肪营养不良的脂肪细胞生物学，发育和分化涉及的其他基因，并确定其在脂肪细胞生物学中的功能。我们将使用最先进的整个外显子组测序来识别这些家族的分子缺陷。第二个目的是确定使用良好的问题，家庭和人群的脂肪营养基因中分子缺陷与代谢发展的关系。这些研究将揭示脂肪营养不良原因以及胰岛素抵抗及其相关的病因所涉及的分子机制。这些新知识可能为开发用于治疗糖尿病，血脂异常和肝脂肪变性的新药物提供靶标。