HYPERCHOLESTEROLEMIA IN CARDIAC FUNCTION, SURVIVAL AND REPAIR
Rokosh Gregg
University Of Louisvillecity: Louisville country: United States (us)
Grant 5R01HL074351-08 from National Heart, Lung, And Blood Institute
Keywords: ing; Acute; Address; Adult; Affect; Animal Model; Animals; Arterial Fatty Streak; Atherosclerosis; base; Biochemical; biological adaptation to stress; biological systems; Blood Vessels; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Physiology; cardiovascular risk factor; Catheterization; Caveolae; Cell Communication; Cell physiology; Cell Therapy; cell type; Cells; Cholesterol; Chronic; Clinic; Clinical; Clinical Trials; Complex; Confocal Microscopy; Coronary Occlusions; Data; Development; Diabetes Mellitus; Diet; Dose; Echocardiography; EFRAC; Endoplasmic Reticulum; endoplasmic reticulum stress; Engraftment; Evaluation; Experimental Models; extracellular; Family suidae; feeding; Funding; Goals; Heart; Heart failure; hemodynamics; Homing; Human; hypercholesterolemia; Hypertension; Immunohistochemistry; improved; In Vitro; in vitro testing; in vivo; Infarction; Injury; insight; Integrins; interdisciplinary approach; interest; Ischemic Preconditioning; LDL Cholesterol Lipoproteins; light microscopy; low density lipoprotein inhibitor; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Matrix Metalloproteinases; Measures; Mediating; Membrane Microdomains; migration; Modeling; modifiable risk; Molecular Biology; Morphology; Motion; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial perfusion; Myocardial tissue; Myocardium; Natural regeneration; novel; Outcome; oxidation; Paracrine Communication; Pathology; Patients; Performance; Physiology; Plasma; Population; pre-clinical; preconditioning; Preparation; pressure; primitive cell; Process; programs; Proteins; Rattus; reconstitution; repaired; Reperfusion Therapy; Research; research study; response; Risk; Risk Factors; Role; Signal Transduction; Specimen; stem; stem cell therapy; Stem cells; Stromal Cell-Derived Factor 1; Structure; Testing; Tissue Extracts; Tissues; translational study; Transplanted tissue; Work
Relevance: Increasing evidence has demonstrated that adult stem/progenitor cells can repair myocardium with functional benefits in animal models of myocardial infarction and heart failure. Small clinical trials of stem cell therapy in human patients with myocardial infarction and ischemic cardiomyopathy have recapitulated these beneficial effects. Recent discovery that heart itself contains cardiac stem cells (CSCs) has sparked intense hope for the development of most promising stem cell therapies for cardiac repair because CSCs are inherently programmed to reconstitute cardiac tissue. However, in the clinical arena patients who need cardiac reparative therapies are mostly associated with cardiovascular risk factors such hypercholesterolemia, diabetes, hypertension etc. With the recent surge of interest in cell therapies for patients, it is important to understand the impacts of these risk factors on stem cell-mediated cardiac repair. Hypercholesterolemia is a most prevalent risk factor and imposes various pathophysiological impacts in the biological system. In this application, we will conduct experiements to investigate the impacts of hypercholesterolemia on CSC-mediated cardiac repaie. We will use both normocholesterolemic and hypercholesterolemic rat models of myocardial infarction. Rats with myocardial infarction will receive CSC therapy. The efficay of CSC therapy for cardiac repair will be assessed using comprehensive evaluation of myocardial performance including echocardiography and hemodynamic pressure-volume catheterization and tissue structure repair including morphology, immunohistochemistry, light and confocal microscopy. Regardless our results are "positive" or "negative", this project will provide novel insights into preclinical framework to develop effective cell-based therapies for cardiac repair in patients with cardiovascular risk factors. Given that plasma cholesterol is a modifiable risk factor and essential for cellular function, understanding the effects of this prevalent risk factor on stem cell- based cardiac repair will have translational and mechanistic importance
Project start date: 2003-07-01
Project end date: 2012-11-30
Budget start date: 1-DEC-2011
Budget end date: 30-NOV-2012
5R01HL074351-08 (2012): $296703
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Rokosh Gregg
THE SDF1-CXCR4 AXIS IN CARDIAC HOMEOSTASIS AND REGENERATION
Rokosh Gregg
University Of Louisvillecity: Louisville country: United States (us)
Grant 5R01HL091202-04 from National Heart, Lung, And Blood Institute
Abstract: The prospect of a cell based therapy for cellular regeneration and functional recovery of the heart was realized with the discovery that stem cells can contribute to myocyte formation in the adult and that these stem cells may also participate in the repair of the heart after injury. It is now clear the heart has inherent regenerative capacity however it is also clear that this capacity is limited. Transplantation of mesenchymal stem cells into patients evokes a reproducible increase in function and provides insight into the potential of this therapeutic approach. To date, little is known of the systems that create and maintain the inherent cardiac stem cells (CSC) and how they participate in day to day function and homeostasis or during and after injury. Stromal cell derived factor 11 (SDF1), and its receptor, CXCR4 are key components of the biological system that regulates hematopoiesis and hematopoietic stem cells. We have found this SDF1-CXCR4 axis in the heart and both are expressed on myocytes and fibroblasts and are functionally coupled to MAPK and AKT signaling that serves a survival function in vitro and in vivo against ischemia reperfusion injury. Both SDF1 and CXCR4 knockouts are embryonic lethal with cardiac defects. These novel findings serve to provide the basis for our hypothesis, that the cardiac SDF1-CXCR4 axis plays a role in cardiac homeostasis through the action on cardiac stem cells, myocytes, and fibroblasts. Myocyte and fibroblast expression of SDF1 and CXCR4 are proposed to serve a similar function for cardiac stem cell maintenance and protection (niche formation) as stromal and osteoblasts do in the bone marrow. The effectiveness of this system in protecting and maintaining the myocardium with stress or injury is limited due to attenuated SDF1-CXCR4 signaling by desensitization of SDF1-CXCR4 signaling. We propose this effectiveness may be increased by increasing the number of receptors and/or limiting desensitization of SDF1- CXCR4 signaling. The following Aims seek to further define the role of the SDF1-CXCR4 axis in cardiac homeostasis and regeneration and to determine how CSC function in cardiac regeneration can be enhanced through optimization of CXCR4 signaling as a cell based therapy in cardiac injury. Aim 1 To determine the role that cardiac SDF1-CXCR4 plays in maintaining cardiac homeostasis in myocyte, myofibroblast, and cardiac stem cells. Aim 2 To determine how desensitization/downregulation of SDF1-CXCR4 signaling limits the functionality of cardiac stem cells. Aim 3 To determine whether increasing signaling and signaling efficacy through the SDF1-CXCR4 axis in cardiac stem cells facilitates increased regenerative capacity by administration early and late after MI and IR injury. Aim 4 To determine whether SDF1-CXCR4 synergizes with HGF-cMET and IGF1-IGFR signaling systems to increase functions critical to stem cell engraftment and repair of functional myocardium. The seminal finding that the heart contains a population of stem cells that can contribute to repair of the injured heart has provided new hope for a cell based therapy for cardiac repair. The research described in this proposal will advance our understanding of and provide mechanistic insight into inherent cardiac systems that regulate the function of cardiac stem cells and their relationship with cardiac muscle and supporting cells. Results from these mechanistic studies will provide the impetus to design novels strategies to overcome inherent limitations of cardiac stem cell participation in cardiac regeneration after cardiac injury or with disease
Keywords: Activities of Daily Living; Acute; Address; Adult; adult stem cell; Area; Arrestins; Attenuated; attenuation; autocrine; base; biological adaptation to stress; biological systems; Bone Marrow; Cardiac; Cardiac Myocytes; Cell Maintenance; Cell physiology; Cell Therapy; cell type; Cells; chemokine; Chemotactic Factors; Chemotaxis; Chronic; Cicatrix; Clear Cell; Congenital Heart Defects; Coupled; CXCR4 gene; CXCR4 Receptors; Cytoprotection; desensitization; design; Disease; Down-Regulation; Effectiveness; Embryo; Engraftment; Environment; Fibroblasts; flexibility; Functional disorder; G-Protein-Coupled Receptors; GRK6 gene; Growth Factor Receptors; GTP-Binding Protein Regulators; GTP-Binding Proteins; GTPase-Activating Proteins; Heart; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Homing; IGF1 gene; IGF1R gene; improved; In Vitro; in vivo; Infarction; Infection; Inflammatory; injured; Injury; insight; Ischemia; Knock-out; Knockout Mice; Lead; Maintenance; MAP Kinase Gene; Mediating; Mesenchymal Stem Cell Transplantation; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; Myofibroblast; Natural regeneration; novel; novel strategies; novel therapeutics; Osteoblasts; overexpression; paracrine; Patients; Perception; Phosphotransferases; Play; Process; progenitor; protein function; Proto-Oncogene Proteins c-akt; Rattus; receptor; Recovery of Function; Recruitment Activity; regenerative; repaired; Reperfusion Injury; Reperfusion Therapy; Research; residence; response; response to injury; Role; Seminal; Signal Transduction; Site; stem cell niche; stem cell population; Stem cells; Stress; Stromal Cell-Derived Factor 1; Stromal Cells; Supporting Cell; System; Testing; Therapeutic; therapy development; tissue regeneration; Tissues; trafficking; Transgenic Organisms; Transplantation
Project start date: 2008-09-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01HL091202-04 (2011): $370000