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Bone Marrow Dysfunction as Underlying Mechanism for Impaired Endothelial...

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Titel Bone Marrow Dysfunction as Underlying Mechanism for Impaired Endothelial Progenitor Cell Mobilization
Looptijd 06 / 2007 - onbekend
Status Afgesloten
Onderzoeknummer OND1326299
Leverancier gegevens Website ZonMw

Samenvatting (EN)

To address the following research questions:1 Does the presence of diabetes reduce circulating EPC levels and impair EPC mobilization in response to a mobilizing stimulus? 2 Is impaired EPC mobilization under diabetic conditions related to reduced bone marrow nitric oxide availability?3 Does hyperglycaemia induce dysfunction of the bone marrow in vitro?4 Does the bone marrow of patients prone to developing cardiovascular disease (CVD) have an impaired capacity to support and release Endothelial Progenitor Cells (EPC)?5 Is the bone marrow nitric oxide (NO) production decreased, or NO availability reduced by NO counteracting radical oxygen species (ROS) in patients prone to developing CVD?6 Are other factors in the bone marrow environment known to be involved in progenitor-cell mobilization (cytokines, adhesion molecules and MMPs) dysregulated in the bone marrow of patients prone to developing CVD, which may contribute to an impaired EPC mobilization? Background: Circulating Endothelial Progenitor Cells (EPC) contribute to endothelial repair and neovascularization, thereby protecting against atherosclerosis and ischemic vascular disease. Various risk factors for cardiovascular disease such as diabetes mellitus are associated with decreased levels of circulating EPC. The underlying causes of reduced EPC levels largely remain to be established. Since EPC originate from the bone marrow and require release into the circulation, reduced EPC levels may be a consequence of impaired EPC mobilization from the bone marrow. Many factors regulate the release of progenitor cells from the bone marrow, including nitric oxide production by bone marrow stromal cells. Nitrix oxide (NO) production in vascular endothelium is known to be impaired in patients at high cardiovascular risk. Hypothesis: The presence of risk factors for cardiovascular disease such as diabetes mellitus induces a dysfunction of the bone marrow environment involving reduced nitric oxide availability, which impairs the release of atheroprotective endothelial progenitor cells.Research Questions:1 Does the presence of diabetes reduce circulating EPC levels and impair EPC mobilization in response to a mobilizing stimulus? 2 Is impaired EPC mobilization under diabetic conditions related to reduced bone marrow nitric oxide availability?3 Does hyperglycaemia induce dysfunction of the bone marrow in vitro?4 Does the bone marrow of patients prone to developing cardiovascular disease (CVD) have an impaired capacity to support and release Endothelial Progenitor Cells (EPC)?5 Is the bone marrow nitric oxide (NO) production decreased, or NO availability reduced by NO counteracting radical oxygen species (ROS) in patients prone to developing CVD?6 Are other factors in the bone marrow environment known to be involved in progenitor-cell mobilization (cytokines, adhesion molecules and MMPs) dysregulated in the bone marrow of patients prone to developing CVD, which may contribute to an impaired EPC mobilization? Approach: First, the influence of diabetes on circulating EPC levels and cytokine (G-CSF+SCF)-induced EPC mobilization will be assessed in streptozotocin-induced (Type I) diabetic mice and ob/ob transgenic (type II) diabetic mice. Also, the bone-marrow (and specifically the bone marrow stromal cells) of these mice will be assessed for NO-production and availability. To further verify a role for NO, NO-availability will be pharmacologically modulated in diabetic mice, and the influence of hyperglycaemia on the capacity of bone marrow stromal cells to support and mobilize progenitor cells will be assessed in an in vitro co-culture model using human cells.Using this in vitro co-culture model, human bone marrow from patients with manifest cardiovascular disease and from controls without manifest CVD will be compared for their capacity to support and release progenitor cells. The bone marrow samples will also be analyzed for markers of NO production and NO-counteracting radical oxygen species; and again the effect of NO/ROS modulation. Finally, these bone marrow samples will be analyzed for various other factors known to play a role in EPC mobilization.Working plan:Most of the required human samples have been gathered in a previous project. Also, some preliminary work has been performed, which indeed showed reduced EPC levels and impaired EPC mobilization in diabetic mice. The technique of human bone marrow in vitro co-culturing assay will be acquired by the AGIKO-candidate at a collaborating laboratory at Cornell University in New York, United States in 2007. The AGIKO-candidate will work full-time on research until 1 september 2007, followed by a period of combining clinical training (0,8fte) with a research position (0,2 fte) with assistance of two research technicians.

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Classificatie

A22000 Veeteelt
D21800 Immunologie, serologie

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