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

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.
摘要

项目成果

期刊论文数量(0)
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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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