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Role of PPARgamma in the interstitial fluid volume regulation and contribution to cardiovascular complications of TZDs

Objective

Thiazolidinediones (TZDs) are clinically proven insulin sensitizers with anti-inflammatory benefits used in the therapy of type 2 diabetes mellitus (T2DM) and atherosclerosis. TZDs can activate a transcription factor, the peroxisome proliferator-activated receptor gamma (PPARg). PPARg regulates expression of several genes involved in inflammatory pathways, lipid transport and carbohydrate metabolism. Antidiabetic effects of TZDs have been coupled to macrophages, since tissue macrophages can produce inflammatory mediators which can reduce insulin sensitivity leading to T2DM and its cardiovascular complications. Administration of TZDs spreaded rapidly recently, although serious secondary effects as fluid retention and ischemic heart disease have questioned the clear benefits of non-selective PPAR activation by TZDs in the medication of T2DM and related disorders. Kidney PPAR positively regulates sodium and water resorbtion, therefore TZD-induced fluid retention can be due to the activation of PPARγ in the kidney collecting ducts. Fluid retention can lead to backward heart failure, therefore we think that kidney PPAR is the origin of unwanted cardiac TZD effects. To test this novel hypothesis we propose a cross-disciplinary research project involving molecular genetics, in vivo imaging, and gene engineered animal models targeting the molecular mechanisms behind the cardiovascular complications of TZDs. We will determine also the contribution of tissue specific PPAR mutations to water retention and ischemic heart disease. Molecular mechanisms behind T2DM and its cardiovascular complications are among the most important and timeliness research areas in Europe, due to the growing T2DM prevalence. Understanding TZD side effects will contribute to new treatment strategies of T2DM. The success of this proposal will increase European competitiveness and will produce long term synergies and structuring community research effects.

Field of science

  • /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug
  • /natural sciences/chemical sciences/inorganic chemistry/inorganic compounds
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/genetics and heredity
  • /medical and health sciences/clinical medicine/endocrinology/diabetes
  • /social sciences/social and economic geography/transport
  • /natural sciences/biological sciences/molecular biology/molecular genetics
  • /medical and health sciences/clinical medicine/cardiology/cardiovascular diseases/arteriosclerosis

Call for proposal

FP7-PEOPLE-IEF-2008
See other projects for this call

Funding Scheme

MC-IEF - Intra-European Fellowships (IEF)

Coordinator

CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.)
Address
Calle Melchor Fernandez Almagro 3
28029 Madrid
Spain
Activity type
Research Organisations
EU contribution
€ 154 102,06
Administrative Contact
Luzma Garcia Piqueres