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（由申请人提供）：肥胖仍然是美国的一个主要健康问题，并导致糖尿病、血脂异常和胰岛素抵抗等代谢并发症，类似的并发症也发生在以部分（家族性部分脂肪代谢障碍，FPL）或几乎完全性为特征的家族性脂肪代谢障碍患者中。（先天性全身性脂肪营养不良，CGL）体内脂肪缺乏在过去几年中，CGL 的几个基因（AGPAT2、BSCL2、CAV1 和）。 PTRF）；FPL（LMNA、PPARG、AKT2、CIDEC 和 PLIN1）；下颌骨发育不良（MAD；LMNA 和 ZMPSTE24）；自身炎症（PSMB8）；矮小综合征（身材矮小、过度伸展/疝气、眼部凹陷、Rieger 异常和出牙延迟； PIK3R1）；和 MDP（下颌发育不全、耳聋和已鉴定出与早老样特征）综合征（POLD1）相关的脂肪营养不良，然而，来自大约 200 个具有 CGL、MAD 和尤其是 FPL 突变的受影响受试者缺乏这些基因，这表明许多极其罕见的脂肪营养不良品种的遗传基础。 SHORT 和新生儿早衰综合症仍然未知，因此，本提案的首要目的是确定导致脂肪细胞生物学、发育和分化的其他基因。我们将使用最先进的全外显子组测序来识别这些家族的分子缺陷，并确定它们在脂肪营养不良基因中的分子缺陷与代谢紊乱之间的关系。 -表型先证者、家庭和人群将揭示脂肪营养不良、胰岛素抵抗及其相关疾病的分子机制。这一新知识可能为开发新的治疗药物提供目标。糖尿病、血脂异常和肝脂肪变性。