MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM
Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 5P01HL055782-050002 from National Heart, Lung, And Blood Institute
Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject
Project start date: 2000-09-01
Project end date: 2001-08-31
Sponsored Links Excellgen http://Excellgen.com
Markers And Mechanisms Of Vascular Disease In Diabetes
Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 5P01HL055782-10 from National Heart, Lung, And Blood Institute IRG: HLBP
Abstract: Vascular Disease is the leading cause of complications and death in patients with diabetes. Risk markers and underlying mechanisms have not been fully elucidated, and may differ from those in non-diabetic individuals. The unifying theme for the Program Project is that hyperglycemia and insulin resistance alter a number of biological processes which interact in vicious cycles to accelerate atherogenesis and are consequently major underlying risk factors for vascular disease. The overall objectives are to define these unique processes and to elucidate underlying biochemical, metabolic, and genetic determinants of vascular disease complications in diabetes. Over the past 4 years, we have collaborated with the DCCT/EDIC Study Group, and have made novel observations regarding vascular disease pathogenesis in Type I Diabetes. This work has focused our studies on specific pathogenic processes. We will also incorporate a Type 2 Diabetes cohort from the VA Cooperative Study, "Glycemic Control and the Complications of Diabetes, Type 2", with high vascular disease event rates. These collaborations provide a unique opportunity to address the pathogenesis of accelerated atherogenesis in the two main types of diabetes, and will greatly augment the scientific knowledge that will be gained in the conduct of these world-class prospective trials. The Program Project has 4 projects and 3 cores. Project 1 will assess lipoproteins, glycoxidative stress, and inflammation as risk factors in studies involving Type 1 and 2 Diabetes patients and cultured cell systems. Based on preliminary data, changes in the NMR lipoprotein subclass profile will be emphasized. Project 2 will elucidate interactions between inflammation, modifications of lipoproteins, and autoimmunity in vascular disease risk. These novel concepts are also based upon exciting preliminary data pertaining to LDL-antibody complexes. Project 3 will pursue interesting preliminary data and define the role of the kallikrein-kinin system in vascular disease complications, with effects on mitogenesis and matrix production. Project 5 will assess the role of the Insulin Resistance Syndrome and novel factors secreted from adipocytes in the pathophysiology of biochemical risk factors and cardiovascular complications. Cores include an Biostatistics and Epidemiology which will link with the trials data coordinating centers, and Molecular and Statistical Genetics Core. There is true synergism among the projects at both scientific and logistical levels. The Program Project design allows for interactions among multi-disciplinary investigators studying the same cohorts, which will define how multiple pathological processes interact at the level of the arterial wall to promote atherosclerosis.
Keywords: cardiovascular disorder epidemiology, diabetes mellitus, diabetes risk, diabetic angiopathy, clinical research
Project start date: 1996-09-30
Project end date: 2008-08-31
5P01HL055782-10 (2005): $1894024
5P01HL055782-09 (2004): $1849846
5P01HL055782-08 (2003): $1807267
5P01HL055782-07 (2002): $1385266
MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN DIABETES
Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 5P01HL055782-100002 from National Heart, Lung, And Blood Institute
Abstract: High levels of immune complexes (IC) containing oxLDL predict the development of macrovascular complications in type 1 diabetes (DM) and are associated with coronary artery disease (CAD) in type 2 DM. Data obtained during the on-going funding period shows that the levels of oxLDL-IC are significantly associated with internal carotid intima-medial thickness (p<0.001, n=853) and are significantly increased in type 1 DM with micro/macroalbuminuria and moderate/severe retinopathy, compared with levels of LDL-IC in patients with normalalbuminuria or mild retinopathy (p<0.013 and 0.0006, respectively). The levels of LDL-IC are strongly correlated with serum Apo B levels, serum Lp(a) levels and serum triglycerides (p<0.0001, n=853) and have also a significant direct correlation (p<0.0001, n=854) with C-reactive protein and with soluble ICAM-1 (p<0.02, n=455). LDL-IC correlate as well with Hb A1c (p<0.005, n=888), suggesting that glycemic control will impact the formation of LDL-IC. We have also demonstrated in patients with micro or macroalbuminuria that antibodies (Ab) against ox-LDL isolated from oxLDL-IC have a higher affinity than the free Ab present in sera of the same patients. This suggests that one critical factor determining the pathogenicity of oxLDL-IC is the synthesis of oxLDL Ab of moderate affinity, able to form stable IC with pro-inflammatory potential. Because Chlamydia pneumonia has been shown to have a strong epidemiological correlation with CAD and one of its major antigens is a cell wall lipopolysaccharide (LPS), that when released into circulation is transported by lipoproteins, we plan to investigate whether chlamydia LPS is present in IC purified from sera of diabetic patients. The main goal of this proposal is to compare the levels of soluble adhesion molecules (sCAM) and the levels and characteristics of LDL-IC isolated from the sera of a type 2 DM cohort (Prospective VA Cooperative Trial) under intensive or standard glycemic control. We hypothesize that, similarly to type 1 DM, LDL-IC in type 2 DM have pro-inflammatory characteristics and are associated with micro and macrovascular complications. We further hypothesize that intensive glycemic control will impact the formation of IC and the release of CAMs into the circulation. We also propose to determine whether or not patients from the DCCT/EDIC cohort (type 1 DM) and VA cohort 2 (type 2 DM) that develop macrovascular disease, retinopathy and micro/macro-albuminuria have a higher incidence of chronic C. pneumoniae infection and to characterize the IC present in the serum of patients from both cohort 1 and 2 that develop macrovascular disease/nephropathy/retinopathy for oxLDL, oxLDL-Lp(a), AGE-LDL, Chlamdial-LPS or DNA, as well as Ab against these antigens. We will also determine the affinity and isotype distribution of Ab isolated from IC, to evaluate their pro-inflammatory potential. Finally, we will assess possible pathogenic mechanisms triggered by these IC by investigating their ability to induce accumulation of cholesterol in macrophages, kidney mesangial cells and retinal pericytes and to activate these cells leading to the expression of cytokines, sCAM and metalloproteinases. Incorporation of our study into the Program allows us to compare LDL-IC levels with the inflammatory markers and endothelial cell dysfunction markers measured in other projects and that will result in a better understanding of the significance of auto-immune responses to modified forms of LDL to the pathogenesis of atherosclerosis in diabetes.
Keywords: autoimmune disorder, blood lipoprotein metabolism, immune complex, low density lipoprotein, noninsulin dependent diabetes mellitus, bacterial antigen, blood glucose, cardiovascular disorder epidemiology, cell adhesion molecule, chlamydial disease, cholesterol, diabetic angiopathy, inflammation, lipopolysaccharide, macrophage, oxidized lipid, vascular endothelium, clinical research, human subject
MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM
Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 5P01HL055782-040002 from National Heart, Lung, And Blood Institute
Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject
Project start date: 1999-09-01
Project end date: 2000-08-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Maria F Lopes-virella
MACROPHAGE ACTIVATION AND LIPOPROTEIN METABOLISM
Maria F Lopes-virella, Professor
Medicinemedical University Of South Carolina
office Of Research And Sponsored Programs
charleston, Sc 29425
Grant 5R01HL046815-06 from National Heart, Lung, And Blood Institute IRG: MET
Abstract: We have demonstrated that the uptake of LDL-containing immune complexes (LDL-IC) by human monocyte-derived macrophages induces the transformation of these cells into foam cells and promotes their activation leading to a paradoxical increase in LDL receptor cell surface expression and to the release of cytokines. In this proposal we plan to analyze the molecular mechanisms responsible for the increase in LDL receptor cell surface expression. We will determine whether the increase in LDL receptor expression, observed in human macrophages stimulated by LDL-containing immune complexes (LDL-IC), is due to increased transcription of the LDL receptor gene, increased mRNA stability, increased mRNA translation, decreased LDL receptor protein degradation or increased translocation of the LDL receptor protein to the cell membrane. We will also investigate whether this increase in LDL receptor expression is secondary to a decrease in the intracellular cholesterol regulatory pool and if so, whether the depletion in this regulatory pool is secondary to enhanced sterol mobilization to the ACAT substrate pool. Furthermore, we will determine whether factors released during macrophage activation mediate or facilitate the increase in LDL receptor cell surface expression. We will also investigate whether the stimulation of LDL receptor cell surface expression is a consequence of the uptake of the LDL-containing immune complexes by a specific Fc receptor subtype (Fc-gamma-RI, Fc-gamma-RII or Fc-gamma-RIII). Since HMGCoA reductase activity and LDL receptor activity usually have a coordinate regulation, we will determine whether HMGCoA reductase activity is also increased in LDL-IC-stimulated macrophages. This project will involve cell culture, cell isolation and cell fractionation procedures, studies of intracellular lipid metabolism, receptor binding studies, immunoblotting and molecular biology techniques. Our overall objective is to provide insight into the mechanisms by which anti-LDL antibodies and macrophage activation may contribute to the development(acceleration of the arteriosclerotic process
Keywords: biological signal transduction, blood lipoprotein metabolism, leukocyte activation /transformation, low density lipoprotein receptor, macrophage, receptor expression cholesterol, enzyme activity, enzyme inhibitor, genetic regulation, genetic regulatory element, genetic transcription, immune complex, mitogen activated protein kinase, reporter gene, second messenger, transcription factor DNA footprinting, antisense nucleic acid, gel mobility shift assay, human tissue, northern blotting, polymerase chain reaction, tissue /cell culture, western blotting
Project start date: 1994-08-01
Project end date: 2001-11-30
5R01HL046815-06 (2001): $235954
5R01HL046815-05 (2000): $229081
2R01HL046815-04A2 (1999): $225409
BIOMARKERS OF VASCULAR DISEASE PROGRESSION IN TYPE 1 DIABETES MELLITUS
Maria F Lopes-virella, Staff Physician
Medical University Of South Carolina, 19 Hagood Ave., Suite 606, Charleston, Sc 29425
Grant 3R01DK081352-02S1 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The NIH has announced the availability of Recovery Act Funds for Competitive Revision Applications (NOT-OD-09-058). The goal of our parent RO1 is to establish a panel of biomarkers for endothelial cell dysfunction/ inflammation/ fibrinolysis that may identify patients with type 1 diabetes at high risk to develop complications. To accomplish this goal, we are measuring circulating levels of cell adhesion molecules (CAM), IL6, TNF, CRP, PAI-1, and fibrinogen in samples from the DCCT/EDIC cohort, collected longitudinally over 20 years. One of the limitations of this work is the lack of a control group that will allow us to establish the normal values for this population. We recently learned that a healthy age and gender matched group was recruited within the 28 centers of the DCCT/EDIC study to serve as a control for the carotid ultrasound studies performed in the cohort. We received serum/plasma samples from these subjects (N=620) and we now propose as Aim 1 of this Competitive Revision to measure VCAM-1, ICAM-1, E-selectin, PAI-1, fibrinogen, CRP, IL-6, and soluble tumor necrosis factor receptors in these samples. We will compare the concentrations of the biomarkers measured in this group of control subjects with those of a matched group of subjects with type 1 diabetes from the DCCT/EDIC cohort without and with diabetes complications that are being measured in the parent RO1. This will enable us to compare the distribution of biomarkers between a population with and without type 1 diabetes as well as with the subgroup of subjects with type 1 diabetes and complications. While knowledge of the levels of these important bioanalytes in both diabetic patients and controls is critical to evaluate their role as biomarkers, we would also like to expand our previous studies to include determination of two recently identified biomarkers, sphingosine-1-phospate (S1P) and lipoprotein-associated phospholipase A2 (Lp- PLA2) which are known to affect the clotting/fibrinolytic pathways and adhesion molecules/inflammation, respectively, and are independent of the level of other biomarkers. Therefore, in Aim 2, we propose to determine the circulating levels of S1P and Lp-PLA2 in the baseline samples of the subgroup of 636 patients enrolled in the DCCT/EDIC cohort in whom longitudinal measurements of biomarkers will not be performed but who will be used to test/validate the predictive value of the biomarkers risk algorithm developed in the remaining cohort. We will determine whether quantitation of either of these newly discovered biomarkers will increase the predictive power of the algorithm developed in Aim 1 of our parent RO1 and better predict the development of micro- and macrovascular complications in this cohort. Diabetes is associated with an increased incidence of heart disease and limb amputation and it is also one of the major contributors to blindness and kidney disease. These complications of diabetes markedly increase the cost of health care and lead to enormous suffering both to the patients and their families. We do not know how to predict the development of these complications in order to intervene earlier in the course of the disease and prevent their development. These studies will determine if blood levels of selected biomarkers (proteins that are associated with well known metabolic abnormalities in diabetes) can predict which diabetic patients will develop diabetic complications and, thus, identify those patients who will require early intervention to prevent the development of complications
Keywords: 4-Octadecene-1, 3-diol, 2-amino-, (R-(R*, S*-(E)))-; 4-Sphingenine; Adhesion Molecule; Affect; Age; Algorithms; Amputation; Arm; Arteries; Assay; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor Gene; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor 2 Gene; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF-2 Gene; BSF2; BSF2 (B cell stimulating factor 2); BSF2 Gene; Benchmarking; Best Practice Analysis; Bioassay; Biologic Assays; Biological Assay; Blindness; Blood; Blood Coagulation Factor I; Blood Coagulation Factor One; Blood Factor One; Blood Plasma; Blood Vessels; Budgets; C-reactive protein; CD106; CD106 Antigens; CD54 (ICAM 1); CD54 Antigens; CD62E Antigens; Cardiac Diseases; Cardiac Disorders; Cell Adhesion Molecule E-Selectin; Cell Adhesion Molecules; Cell Function; Cell Process; Cell physiology; Cellular Function; Cellular Physiology; Cellular Process; Chronic Disease; Chronic Illness; Classification; Clotting; Coagulation; Coagulation Factor I; Coagulation Factor One; Coagulation Process; Complement; Complement Proteins; Complication; Complications of Diabetes Mellitus; Control Groups; Coronary Disease; Coronary heart disease; Cytokines, Chemotactic; DIF; Data; Development; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Brittle; Diabetes Mellitus, Insulin-Dependent; Diabetes Mellitus, Juvenile-Onset; Diabetes Mellitus, Ketosis-Prone; Diabetes Mellitus, Sudden-Onset; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type I; Diabetes-Related Complications; Diabetic Angiopathies; Diabetic Complications; Diabetic Vascular Complications; Diabetic Vascular Diseases; Diabetic Vascular Disorder; Diagnosis, Ultrasound; Differentiation Factor, B-Cell; Dimensions; Disease; Disease Progression; Disease regression; Disorder; Dysfunction; E-Selectin; ELAM-1; Early treatment; Echography; Echotomography; Endothelial Adhesion Molecule 1; Endothelial Cells; Endothelial Leukocyte Adhesion Molecule-1; Enrollment; Equipment; Evaluation; Event; Extremities; Factor I; Factor One; Family; Fibrinogen; Fibrinolyses; Fibrinolysis; Functional disorder; Funding; Gender; Glycoprotein ICAM 1 (human clone pHRVr1 deblocked protein moiety reduced); Goals; Grant; HPGF; HSF Gene; Health Care Costs; Health Costs; Healthcare Costs; Heart Diseases; Hepatocyte Stimulatory Factor Gene; Hepatocyte-Stimulating Factor; Homologous Chemotactic Cytokines; Hour; Hybridoma Growth Factor; Hybridoma Growth Factor Gene; Hydrolysis; ICAM-1; IDD; IDDM; IFN-beta 2; IFNB2; IFNB2 Gene; IL-6; IL-6 Gene; IL6; IL6 Protein; IL6 gene; INCAM-110; INFLM; Incidence; Inducible Cell Adhesion Molecule 110; Inflammation; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intercellular adhesion molecule 1; Intercrines; Interferon, Beta-2 Gene; Interleukin 6 (Interferon, Beta 2); Interleukin 6 (Interferon, Beta 2) Gene; Interleukin-6; Interleukin-6 Gene; Investigators; Kidney Diseases; Knowledge; LECAM-2; Laboratories; Lead; Learning; Leukocyte Endothelial Cell Adhesion Molecule 2; Limb structure; Limbs; Lipoproteins; Longitudinal Studies; Lp-PLA(2); Lp-PLA2; MGI-2; Matched Group; Measurement; Measures; Medial; Mediating; Medical Imaging, Ultrasound; Metabolic; Method LOINC Axis 6; Methodology; Myeloid Differentiation-Inducing Protein; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nephropathy; Non-Trunk; Normal Range; Normal Values; Obesity; OxLDL; PAI-1; PAI1; PLANH1; Parents; Pathway interactions; Patients; Pb element; Permeability; Phase; Phosphatides; Phospholipids; Physiopathology; Plasma; Plasmacytoma Growth Factor; Plasminogen Activator Inhibitor 1; Play; Population; Predictive Value; Prevention; Protein C; Proteins; Proteins, specific or class, C-reactive; Recovery; Recruitment Activity; Regression; Renal Disease; Research; Research Personnel; Researchers; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Retinal Diseases; Retinal Disorder; Risk; Risk Factors; Role; SIS cytokines; SUBGP; Sampling; Screening procedure; Serine or Cysteine Proteinase Inhibitor Clade E Member 1; Serum, Plasma; Siblings; Specialist; Sphingosine; Subcellular Process; Subgroup; Surrogate End Points; Surrogate Endpoint; Symptoms; Systematics; T1 diabetes; T1D; T1DM; TNF; TNF A; TNF gene; TNFR-Fc fusion protein; TNFSF2; TNR-001; TNT receptor fusion protein; TNTR-Fc; Technology; Testing; Thick; Thickness; Time; Tumor Necrosis Factor Gene; Type 1 Plasminogen Activator Inhibitor; Type 1 diabetes; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Test; Ultrasound, Medical; United States National Institutes of Health; Upper arm; VCAM; VCAM-1; Validation; Vascular Cell Adhesion Molecule; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Disorder; Work; adiposity; biomarker; blood vessel disorder; cell adhesion protein; chemoattractant cytokine; chemokine; chronic disease/disorder; chronic disorder; cohort; coronary disorder; corpulence; corpulency; corpulentia; diabetes; diabetic patient; diagnostic ultrasound; disease/disorder; endothelial leukocyte adhesion molecule; enroll; gene product; glycemic control; heart disorder; heavy metal Pb; heavy metal lead; high risk; imprint; inflammatory marker; instrument; insulin dependent diabetes; insulin resistant; interferon beta 2; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; kidney disorder; lipoprotein-associated phospholipase A(2); lipoprotein-associated phospholipase A2; long-term study; macrovascular complication; macrovascular disease; microvascular complications; microvascular complications of diabetes; microvascular disease; non-diabetic; nondiabetic; novel marker; obese; obese people; obese person; obese population; ox-LDL; oxidized LDL; oxidized low density lipoprotein; parent grant; pathophysiology; pathway; prevent; preventing; public health relevance; recruit; renal disorder; retina disease; retina disorder; retinopathy; screening; screenings; social role; soluble tumor necrosis factor receptor; sonogram; sonography; sound measurement; sphingosine 1-phosphate; type I diabetes; type I diabetic; ultrasound; ultrasound imaging; ultrasound scanning; vascular
Relevance: Diabetes is associated with an increased incidence of heart disease and limb amputation and it is also one of the major contributors to blindness and kidney disease. These complications of diabetes markedly increase the cost of health care and lead to enormous suffering both to the patients and their families. We do not know how to predict the development of these complications in order to intervene earlier in the course of the disease and prevent their development. These studies will determine if blood levels of selected biomarkers (proteins that are associated with well known metabolic abnormalities in diabetes) can predict which diabetic patients will develop diabetic complications and, thus, identify those patients who will require early intervention to prevent the development of complications
Project start date: 2008-09-01
Project end date: 2011-08-31
Budget start date: 25-SEP-2009
Budget end date: 31-AUG-2011
PFA/PA: PAR-07-024
3R01DK081352-02S1 (2009): $410125
5R01DK081352-03 (2010): $506160
5R01DK081352-02 (2009): $441115
MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM
Maria F Lopes-virella, Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 1P01HL055782-020002 from National Heart, Lung, And Blood Institute
Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject
Project start date: 1997-09-15
Project end date: 1998-08-31
MACROPHAGE ACTIVATION AND LIPOPROTEIN METABOLISM
Maria F Lopes-virella, Professor
Medicinemedical University Of South Carolina
office Of Research And Sponsored Programs
charleston, Sc 29425
Grant 5R01HL046815-03 from National Heart, Lung, And Blood Institute IRG: MET
Project start date: 1994-08-01
Project end date: 1998-07-31
5R01HL046815-03 (1996): $217577
MODIFIED LDL, AUTOIMMUNITY AND VASCULAR DISEASE IN IDDM
Maria F Lopes-virella, Professor
Institution:
Grant 1P01HL055782-01A10002 from National Heart, Lung, And Blood Institute
Keywords: atherosclerosis, autoimmune disorder, blood lipoprotein metabolism, insulin dependent diabetes mellitus, low density lipoprotein, autoantibody, cardiovascular disorder epidemiology, cell adhesion molecule, diabetic angiopathy, immune complex, macrophage, clinical research, human subject