Ronald L Dalman
Stanford University
Project start date: 2010-07-01
Project end date: 2015-06-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Ronald L Dalman
MECHANISMS IN INNOVATION IN VASCULAR DISEASE
Ronald L Dalman, Chief, Vascular Division
Stanford University, 340 Panama Street, Stanford, Ca 94305-6203
Grant 1T32HL098049-01A1 from National Heart, Lung, And Blood Institute
Abstract: This program will train 6 postdoctoral fellows annually in mechanisms and Innovation in vascular disease. The program goals include rigorous training in the scientific method, critical analysis, logical reasoning and independent thinking, all within a highly collaborative working group. Trainees will develop a focused area of translational vascular research expertise and will be exposed to a wide range of complementary research techniques. Mentors will provide collegial and productive collaboration, and help to hone skills in oral and written communication, and to instill respect for the responsible conduct of research. Fellows will undergo a minimum two-year education and research program, although we only intend to fund the first year through the institutional T32. Fellows will be encouraged and mentored in their development of funding proposals for the second year. The overarching goal for this program is to produce researchers who are well-schooled in the fundamental problems of vascular disease, and are driven to find innovative strategies to tackle those problems, thereby translating basic research into clinical success. Fellows will receive their training in a multidisciplinary milieu of fundamental, translational and clinical research in vascular biology and disease. The Stanford Cardiovascular Institute (CVI) offers a unique platform by which to train the next generation of basic and translational scientists. Mentors for the proposed program, all members of the CVI, come not only from vascular medicine, but also from materials science, bioengineering, imaging, and health research and policy. Brought together in a collaborative Institute, these scientists share a common interest in the mechanisms behind vascular development and disease
Keywords: Vascular Diseases; Vascular Disorder; blood vessel disorder; innovate; innovation; innovative
Project start date: 2010-07-01
Project end date: 2015-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-08-226
1T32HL098049-01A1 (2010): $119254
EVALUATION OF EXERCISE THERAPY FOR SMALL AAA
Ronald L Dalman, Chief, Vascular Division
Stanford University, 340 Panama Street, Stanford, Ca 94305-6203
Grant 5P50HL083800-04_0003 from National Heart, Lung, And Blood Institute
Abstract: Abdominal aortic aneurysm disease is a common and lethal health problem of older Americans. Substantial evidence links sedentary existence and resulting pro-inflammatory aortic conditions to the pathogenesis of AAA disease. Insights derived from investigations in animal models and high risk patient groups and care of AAA patients have help define our LONG TERM OBJECTIVE; to identify, validate and apply effective nonsurgical therapies to the treatment of AAA disease. The purpose of this proposal is to test the ability of lower extremity exercise to reduce AAA risk, limit small aneurysm progression and modify biologic markers of disease. We have two SPECIFIC AIMS First, we will perform a cross-sectional correlation study to determine whether lifetime physical activity and measured exercise capacity represent independent risk factors for AAA disease. These studies will test our hypothesis that aortic diameter and activity level will be independently and inversely related; that is, abdominal aorta size adjusted for age, will be increased in A) inidividuals completing questionnaires indicating persistently low levels of physical activity or B) have reduced exercise capacity as defined by clinical testing. Second, we will perform a prospective, randomized controlled longitudinal trial of exercise to suppress small AAA progression. The impact of training will be monitored by both serial surveillance ultrasound imaging and surrogage biologic markers and imaging of disease progression. This will test our hypothesis that supervised exercise training will reduce AAA expansion rates and/or diminish surrogate markers of disease progression. To ACHIEVE THESE AIMS we will apply analyze life time physical activity to several hundred patients with the new diagnosis of small AAA disease, measure aortic diameter in a large cohort of patients with previously defined exercise capacity, and apply supervised exercise training to an additional cohort of small aneurysm patients. This application is RELEVANT to public health in that we will test a new and low risk method of preventing the development or progression of AAA disease, a potentially life threatening condition. In addition, we will develop a framework to test, measure and compare the effectiveness of future novel therapies
Keywords: 92-kDa Gelatinase; 92-kDa Type IV Collagenase; Abdomen; Abdominal; Abdominal Aortic Aneurysm; Abdominal aorta structure; Age; American; Aneurysm; Animal Model; Animal Models and Related Studies; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Apoptosis; Apoptosis Pathway; Biologic Marker; Biological Markers; Blood Plasma; Blood Serum; C-reactive protein; Caliber; Cardiovascular; Cardiovascular Body System; Cardiovascular Diseases; Cardiovascular system; Cardiovascular system (all sites); Caring; Cell Death, Programmed; Cells; Cessation of life; Clinical Evaluation; Clinical Testing; Computer Simulation; Computerized Models; Congresses; Correlation Studies; Death; Development; Diagnosis; Diagnosis, Ultrasound; Diameter; Disease; Disease Progression; Disorder; Echography; Echotomography; Evaluation; Event; Exercise; Exercise Test; Exercise Therapy; Exercise stress test; Exercise, Physical; FDG PET; Future; Gelatinase B; Health; Health Care Costs; Health Costs; Healthcare Costs; Hyperemia; INFLM; Image; Imaging Procedures; Imaging Techniques; Individual; Inflammation; Inflammatory; Intervention; Intervention Strategies; Investigation; Legislation; Leiomyocyte; Life; Link; Lower Extremity; Lower Limb; MMP-9; MMP-9 Protein; MMP9; MR Imaging; MR Tomography; MRI; Macrophage Gelatinase; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Markers, Serum; Markers, Surrogate; Mathematical Model Simulation; Mathematical Models and Simulations; Matrix Metalloproteinase-9; Measurement; Measures; Mediating; Medical; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medical Imaging, Ultrasound; Medical center; Membrum inferius; Methods; Models, Computer; Molecular Marker; Monitor; Mononuclear; Morphology; Mortality; Mortality Vital Statistics; Multi-Institutional Clinical Trial; Multi-center clinical study; Multi-center clinical trial; Multi-site clinical study; Multi-site clinical trial; Myocytes, Smooth Muscle; NMR Imaging; NMR Tomography; Newly Diagnosed; Nuclear Magnetic Resonance Imaging; Operation; Operative Procedures; Operative Surgical Procedures; Organ System, Cardiovascular; Participant; Pathogenesis; Patients; Persons; Phase; Physical activity; Physical therapy exercises; Plasma; Population; Populations at Risk; Prevalence; Protein Cleavage; Proteins, specific or class, C-reactive; Proteolysis; Proteomics; Public Health; Questionnaires; Randomized; Reticuloendothelial System, Serum, Plasma; Risk; Risk Factors; Rupture; Screening procedure; Seminal; Serum; Serum Markers; Serum, Plasma; Signature Molecule; Simulation, Computer based; Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; Statistical Correlation; Statutes and Laws; Stratification; Surgical; Surgical Interventions; Surgical Procedure; Surrogate Markers; Technics, Imaging; Testing; Time; Training; Type V Collagenase; Ultrasonic Imaging; Ultrasonogram; Ultrasonography; Ultrasound Test; Ultrasound, Medical; United States; Update; Vascular, Heart; Zeugmatography; abdominal aorta; advanced disease; base; bioimaging; bioimaging/biomedical imaging; biomarker; biomedical imaging; cardiovascular disorder; circulatory system; clinical test; cohort; compare effectiveness; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; design; designing; diagnostic ultrasound; disability; disease risk; disease/disorder; disorder risk; extracellular; fitness; fluorodeoxyglucose PET; fluorodeoxyglucose positron emission tomography; hemodynamics; high risk; imaging; in silico; in vivo; insight; interventional strategy; model organism; multi center clinical study; multi center clinical trial; multi site clinical study; multi site clinical trial; novel; prevent; preventing; prospective; public health medicine (field); randomisation; randomization; randomly assigned; repair; repaired; research clinical testing; screening; screenings; sedentary; sonogram; sonography; sound measurement; surgery; ultrasound; ultrasound imaging; ultrasound scanning; vascular inflammation; virtual simulation
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2010
PFA/PA: RFA-HL-05-001
5P50HL083800-04_0003 (2009): $1058306
AAA DISEASE: MECHANISM, STRATIFICATION AND TREATMENT
Ronald L Dalman, Chief, Vascular Division
Stanford University, 340 Panama Street, Stanford, Ca 94305-6203
Grant 5P50HL083800-05 from National Heart, Lung, And Blood Institute
Abstract: Abdominal aortic aneurysm (AAA) is a common, morbid, and frequently lethal disease of older Americans. Major clinical challenges in AAA disease include the absence of 1) effective non-surgical therapies to prevent progression of early stage disease, and 2) validated biomarkers or efficient imaging indices to monitor disease activity and guide suppressive medical therapies in small aneurysms. Based on extensive prior evidence demonstrating that variable aortic flow and wall shear stress conditions modulate vascular inflammation, this SCCOR proposes to 1) Identify and validate novel biomarkers and imaging strategies for AAA disease stratification, 2) Test the ability of exercise therapy to suppress small AAAs, and 3) Investigate key molecular and cellular events present during experimental AAA evolution to identify and refine novel therapeutic strategies. Project I (Thrombin-Cleaved Osteopontin in AAA) will examine the role of thrombin-cleaved osteopontin and its regulation in AAA, and determine if measurements of specific cleaved forms of osteopontin will serve as useful biomarkers for predicting disease progression. Project II (Signature Protein Profile to Identify AAAs) will develop a custom antibody-based protein array to test whether distinct signature protein profiles can be identified that will correlate with AAA of different sizes, and whether changes in these profiles can predict disease progression and response to intervention. Project III (Hemodynamics in AAA Progression) will characterize the hemodynamics in the infrarenal aorta of patients with AAA, under both resting and exercise conditions, using MRI-based imaging techniques. We will examine how the shape, size, or vessel wall structure of the aortic aneurysm influence the hemodynamic parameters in AAA and test whether these changes in flow and vessel wall characteristics predict disease progression and response to intervention. Project IV (Evaluation of Exercise Therapy in Small AAA) is the key project in this SCCOR application. A prospective randomized trial will be carried out to test whether a supervised and sustained exercise program will reduce the rate of expansion of small AAA in patients. This clinical trial will anchor and connect all the other projects of this SCCOR. The proposed SCCOR will enable many accomplished investigators with complementary expertise to develop a coordinated and integrated approach to analysis, stratification and treatment of AAA disease, and fulfills the SCCOR objective of translating knowledge into clinical practice
Project start date: 2006-05-01
Project end date: 2011-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: RFA-HL-05-001
5P50HL083800-05 (2010): $2756828
5P50HL083800-04 (2009): $2857731
5P50HL083800-02 (2007): $2818882
1P50HL083800-01 (2006): $2860642
MECHANO-BIOLOGIC DETERMINANTS OF AAA DISEASE
Ronald L Dalman, Chief, Vascular Division
Stanford University, 340 Panama Street, Stanford, Ca 94305-6203
Grant 5R01HL064338-08 from National Heart, Lung, And Blood Institute
Abstract: Abdominal aortic aneurysm (AAA) disease is a common and lethal health problem of older Americans. Substantial evidence links sedentary existence and resulting pro-inflammatory aortic hemodynamic conditions to the pathogenesis of AAA disease. Insights derived from in vivo imaging studies in high risk human subjects, AAA patients and animal models are essential to realizing our LONG TERM OBJECTIVE; the discovery and validation of physical and pharmacological interventions capable of reducing AAA risk, progression and treatment morbidity. We have 2 SPECIFIC AIMS First, we will define rest and exercise aortic conditions in ambulatory subjects, patients with small, early AAA and murine models, as well as resting conditions in sedentary patients at high risk for AAA disease (spinal cord injury). These studies will test our hypotheses that I) chronically reduced flow and shear account for increased AAA risk in sedentary patients, ii) exercise improves hemodynamic conditions in small AAA, and III) variable flow models reproduce to scale clinically relevant ranges of hemodynamic conditions. Second, we will track inflammatory cell migration and gene expression in vivo in response to variable flow conditions. These experiments will define how flow loading and accompanying increased shear and tensile forces reduce macrophage delivery, accumulation, proinflammatory gene expression and progenitor cell localization and differentiation. To ACHIEVE THESE AIMS, we will analyze and define human and murine aortic hemodynamic conditions using magnetic resonance (MR) imaging and computer simulations. Hemodynamic influences on macrophage migration, accumulation and regulatory gene expression will be assayed via bioluminescence and MR cellular imaging. Circulating progenitor cell localization and differentiation will be examined via dual staining strategies in chimeric mice
Keywords: Abdomen; Abdominal; Abdominal Aortic Aneurysm; Accounting; American; Aneurysm; Animal Model; Animal Models and Related Studies; Aorta; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Assay; Bioassay; Biologic Assays; Biologic Marker; Biological Assay; Biological Markers; Bioluminescence; Blood Vessels; Blood flow; Cell Locomotion; Cell Migration; Cell Movement; Cells; Cellular Migration; Cellularity; Chronic; Clinical Trials; Clinical Trials, Unspecified; Computer Simulation; Computerized Models; Condition; Disease; Disorder; Drug Therapy; Effectiveness; Exercise; Exercise, Physical; Gene Expression; Genes, Regulator; Genetic; Genetic Risk; Health; Human; Human, General; INFLM; Image; Infiltration; Inflammation; Inflammatory; Intervention; Intervention Strategies; Invasive; Kinetic; Kinetics; Label; Link; Lower Extremity; Lower Limb; MR Imaging; MR Tomography; MRI; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Mammals, Mice; Man (Taxonomy); Man, Modern; Mathematical Model Simulation; Mathematical Models and Simulations; Medial; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Membrum inferius; Methods; Mice; Modeling; Models, Computer; Molecular; Molecular Marker; Morbidity; Morbidity - disease rate; Mother Cells; Motility; Motility, Cellular; Murine; Mus; Muscle, Involuntary; Muscle, Smooth; Myelopathy, Traumatic; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Operation; Operative Procedures; Operative Surgical Procedures; Pathogenesis; Patients; Pattern; Pharmacotherapy; Physiologic pulse; Predisposition; Progenitor Cells; Public Health; Pulse; Pulse taking; Purpose; Range; Recommendation; Regulation; Regulator Genes; Relative; Relative (related person); Reporter; Rest; Risk; Risk Factors; Rodent Model; SCI Patients; SMC; SMC1beta protein, mouse; SMCB protein, mouse; Signature Molecule; Simulation, Computer based; Smc1l1 protein, mouse; Smc1l2 protein, mouse; Smooth muscle (tissue); Spinal Cord Trauma; Spinal Trauma; Spinal cord injured; Spinal cord injuries; Spinal cord injury; Spinal cord injury patients; Staining method; Stainings; Stains; Stem cells; Surgical; Surgical Interventions; Surgical Procedure; Surrogate End Points; Surrogate Endpoint; Susceptibility; Testing; Transcriptional Regulatory Elements; Validation; Zeugmatography; aorta aneurysm; biomarker; cell imaging; cell motility; cellular imaging; cigarette smoking; clinical investigation; clinical relevance; clinically relevant; computational modeling; computational models; computational simulation; computer based models; computerized modeling; computerized simulation; design; designing; disease/disorder; experience; experiment; experimental research; experimental study; hemodynamics; human subject; imaging; improved; in silico; in vivo; inhibitor; inhibitor/antagonist; insight; interventional strategy; mSMCB protein, mouse; macrophage; migration; model organism; mouse Smc1l1 protein; mouse Smc1l2 protein; public health medicine (field); regulatory gene; repair; repaired; research study; response; sedentary; shear stress; smoke cigarette; structural maintenace of chromosomes 1-like 2 (S. cerevisiae) protein, mouse; structural maintenance of chromosomes 1-like 1 (S. cerevisiae), mouse; surgery; trafficking; trans acting element; vascular; virtual simulation
Project start date: 1999-09-30
Project end date: 2010-06-30
Budget start date: 1-JUL-2008
Budget end date: 30-JUN-2010
5R01HL064338-08 (2008): $0
5R01HL064338-07 (2007): $265617
5R01HL064338-06 (2006): $273236
Sponsored Links Excellgen http://Excellgen.com
2R01HL064338-05A2 (2005): $279577
Ronald L Dalman
Stanford University
Project start date: 2012-01-01
Project end date: 2013-12-30
MECHANO-BIOLOGIC DETERMINANTS OF EXPERIMENTAL AAA
Ronald L Dalman, Associate Professor
Surgerystanford University
stanford, Ca 94305
Grant 5R01HL064338-04 from National Heart, Lung, And Blood Institute IRG: ZHL1
Keywords: aorta aneurysm, disease /disorder model, gene expression, hemodynamics, inflammation abdomen, biomechanics, blood flow, elastase blood flow measurement, immunocytochemistry, in situ hybridization, intravital microscopy, laboratory rat, nucleic acid probe
Project start date: 1999-09-30
Project end date: 2004-08-31
5R01HL064338-04 (2002): $234600
5R01HL064338-03 (2001): $234600
5R01HL064338-02 (2000): $234600