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:10119702
- 负责人:
- 金额:$ 68.84万
- 依托单位:
- 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 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AKT2 geneAcanthosis NigricansAdipose tissueAffectBSCL2 geneBiochemicalBiologicalBiological ModelsBiological ProcessBody fatCAV1 geneCell LineCell modelCessation of lifeCharacteristicsClinicalDefectDevelopmentDiabetes MellitusDiseaseDual-Energy X-Ray AbsorptiometryDyslipidemiasDysplasiaEtiologyFBN1Familial generalized lipodystrophyFamilial partial lipodystrophyFamilyFamily memberFatty LiverFibroblastsGenesGeneticGenomicsGenotypeGoalsGrantHIV-Associated Lipodystrophy SyndromeHealthHerniaHypertriglyceridemiaInsulin ResistanceKnowledgeLaboratoriesLeadLightLipodystrophyMagnetic Resonance ImagingMandibleMeasurementMendelian disorderMental DepressionMetabolicMolecularMolecular GeneticsMorbidity - disease rateMutationNOTCH3 geneNon-Insulin-Dependent Diabetes MellitusObesityPPARG genePathway interactionsPatientsPhenotypePolymerase Chain ReactionProcessRieger syndromeRoleSkinSkinfold ThicknessSyndromeTechnologyTeethingTherapeutic InterventionTissuesUnited StatesVariantWiedemann-Rautenstrauch syndromeWorkadipocyte biologyadipocyte differentiationautoinflammatorybasecausal variantclinical phenotypedeafnessdesignearly onsetgene functiongenetic approachgenetic pedigreegenetic variantgenome sequencinggenomic locusin vitro Assayinsightlymphoblastmetabolic abnormality assessmentnew therapeutic targetnext generation sequencingnovelnovel therapeuticsprobandrecruittranscriptometranscriptome sequencingwhole genome
项目摘要
Abstract
Obesity remains a major health problem in the United States and causes metabolic complications
such as type 2 diabetes mellitus, dyslipidemia, hepatic steatosis and insulin resistance. Similar
complications also occur in patients with familial lipodystrophies characterized by partial (familial
partial lipodystrophy, FPLD) or almost complete (congenital generalized lipodystrophy, CGL) lack
of body fat. In the last two decades, several causal genes have been discovered for lipodystrophy
syndromes including AGPAT2, BSCL2, CAV1 and CAVIN1 for CGL; LMNA, PPARG, ADRA2A,
AKT2, CIDEC, LIPE, MFN2, PCYT1A and PLIN1 for FPLD; LMNA and ZMPSTE24 for
mandibuloacral dysplasia (MAD); PSMB8 for autoinflammatory lipodystrophy; PIK3R1 for short
stature, hyperextensibility/hernias, ocular depression, Rieger anomaly and teething delay (SHORT)
syndrome; POLD1 for MDP (mandibular hypoplasia, deafness and progeroid features) syndrome;
and FBN1, CAV1, and POL3RA for Weidemann-Rautenstrauch syndrome (WRS). Our laboratory
has been at the forefront of these studies and identified AGPAT2, PPARG, ZMPSTE24, and
PSMB8 genes for various types of lipodystrophies. In addition, during the last five years, we have
identified novel lipodystrophy genes, such as ADRA2A, POLR3A, PRRT3, MTX2, TOMM7,
COL3A1 and NOTCH3; and novel variants, such as heterozygous p.R571S and homozygous
p.R545H in LMNA, and heterozygous p.Q142* and p.F160* in CAV1 associated with unique
lipodystrophy syndromes. However, the genetic basis of about 210 extremely rare patients with
various subtypes of genetic lipodystrophies, including 179 pedigrees with FPLD phenotype, remains
unknown. Thus, the first aim of this proposal is to identify novel gene(s)/variants involved in
adipocyte biology, development and differentiation that cause lipodystrophies and to determine their
function in adipocyte biology by using cellular model system. We will use the state-of-the-art whole
genome sequencing combined with tissue transcriptome analysis to identify the molecular defects.
The second aim is to ascertain relationships between molecular defects in lipodystrophy genes with
metabolic derangements using well-phenotyped probands and families. We will conduct deep
phenotyping using skinfold thickness measurements, dual-energy X-ray absorptiometry for regional
body fat, whole-body magnetic resonance imaging for body fat distribution, and biochemical
parameters for metabolic complications. 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 metabolic complications of
obesity including diabetes, dyslipidemias and hepatic steatosis.
抽象的
肥胖仍然是美国的一个主要健康问题并导致代谢并发症
例如2型糖尿病、血脂异常、肝脂肪变性和胰岛素抵抗。相似的
并发症也发生在以部分(家族性)脂肪营养不良为特征的家族性脂肪营养不良患者中。
部分脂肪营养不良,FPLD)或几乎完全(先天性全身性脂肪营养不良,CGL)缺乏
身体脂肪。在过去的二十年中,已经发现了一些脂肪营养不良的致病基因
综合征包括 CGL 的 AGPAT2、BSCL2、CAV1 和 CAVIN1; LMNA、PPARG、ADRA2A、
用于 FPLD 的 AKT2、CIDEC、LIPE、MFN2、PCYT1A 和 PLIN1; LMNA 和 ZMPSTE24 用于
下颌骨发育不良(MAD); PSMB8 用于自身炎症性脂肪营养不良;简称PIK3R1
身材、伸展过度/疝气、眼部凹陷、Rieger 异常和出牙延迟(简短)
综合症; POLD1 用于 MDP(下颌发育不全、耳聋和早衰特征)综合征;
以及针对 Weidemann-Rautenstrauch 综合征 (WRS) 的 FBN1、CAV1 和 POL3RA。我们的实验室
一直处于这些研究的前沿,并确定了 AGPAT2、PPARG、ZMPSTE24 和
PSMB8 基因用于各种类型的脂肪营养不良。此外,在过去的五年里,我们还
鉴定出新的脂肪营养不良基因,例如 ADRA2A、POLR3A、PRRT3、MTX2、TOMM7、
COL3A1 和 NOTCH3;以及新的变异体,例如杂合子 p.R571S 和纯合子
LMNA 中的 p.R545H,以及 CAV1 中与独特相关的杂合 p.Q142* 和 p.F160*
脂肪营养不良综合征。然而,大约 210 名极其罕见的患者的遗传基础
遗传性脂肪营养不良的各种亚型,包括 179 个具有 FPLD 表型的家系,仍然存在
未知。因此,该提案的首要目标是识别参与的新基因/变体
导致脂肪营养不良的脂肪细胞生物学、发育和分化,并确定其
通过使用细胞模型系统在脂肪细胞生物学中发挥作用。我们将采用最先进的整体
基因组测序结合组织转录组分析来识别分子缺陷。
第二个目标是确定脂肪营养不良基因的分子缺陷与
使用表型良好的先证者和家族进行代谢紊乱。我们将深入开展
使用皮褶厚度测量、双能 X 射线吸收测定法进行区域表型分析
身体脂肪、身体脂肪分布的全身磁共振成像和生化
代谢并发症的参数。这些研究将揭示相关的分子机制
导致脂肪营养不良、胰岛素抵抗及其相关疾病。这个新的
知识可能为开发治疗代谢并发症的新药提供目标
肥胖包括糖尿病、血脂异常和肝脂肪变性。
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)
专利数量(0)
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Abhimanyu Garg其他文献
Abhimanyu Garg的其他文献
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{{ truncateString('Abhimanyu Garg', 18)}}的其他基金
Long term efficacy and safety of orlistat for type 1 hyperlipoproteinemia: a randomized, double-blind, placebo-controlled trial
奥利司他治疗 1 型高脂蛋白血症的长期疗效和安全性:一项随机、双盲、安慰剂对照试验
- 批准号:
10570530 - 财政年份:2023
- 资助金额:
$ 68.84万 - 项目类别:
Genetic and Metabolic Basis of Familial Lipodystrophies
家族性脂肪营养不良的遗传和代谢基础
- 批准号:
9054839 - 财政年份:2015
- 资助金额:
$ 68.84万 - 项目类别:
Genetic and Metabolic Basis of Familial Lipodystrophies
家族性脂肪营养不良的遗传和代谢基础
- 批准号:
9237269 - 财政年份:2015
- 资助金额:
$ 68.84万 - 项目类别:
Genetic and Metabolic Basis of Familial Lipodystrophies
家族性脂肪营养不良的遗传和代谢基础
- 批准号:
10264148 - 财政年份:2015
- 资助金额:
$ 68.84万 - 项目类别:
Genetic and Metabolic Basis of Familial Lipodystrophies
家族性脂肪营养不良的遗传和代谢基础
- 批准号:
10473862 - 财政年份:2015
- 资助金额:
$ 68.84万 - 项目类别:
Phase 2 Study of Obeticholic Acid for Lipodystrophy Patients
奥贝胆酸治疗脂肪营养不良患者的 2 期研究
- 批准号:
8817627 - 财政年份:2014
- 资助金额:
$ 68.84万 - 项目类别:
Phase 2 Study of Orlistat and SLX-4090 for Type I Hyperlipoproteinemia
奥利司他和 SLX-4090 治疗 I 型高脂蛋白血症的 2 期研究
- 批准号:
8518255 - 财政年份:2012
- 资助金额:
$ 68.84万 - 项目类别:
Phase 2 Study of Orlistat and SLX-4090 for Type I Hyperlipoproteinemia
奥利司他和 SLX-4090 治疗 I 型高脂蛋白血症的 2 期研究
- 批准号:
8217878 - 财政年份:2012
- 资助金额:
$ 68.84万 - 项目类别:
Genetic and Metabolic Basis of Familial Lipodystrophies
家族性脂肪营养不良的遗传和代谢基础
- 批准号:
7992512 - 财政年份:2010
- 资助金额:
$ 68.84万 - 项目类别:
NOVEL THERAPIES FOR METABOLIC COMPLICATION IN PATIENTS WITH LIPODYSTROPHIES
脂肪营养不良患者代谢并发症的新疗法
- 批准号:
7606355 - 财政年份:2007
- 资助金额:
$ 68.84万 - 项目类别:
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