Ling Wei
Emory University
Project start date: 2010-02-01
Project end date: 2015-01-31
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Ling Wei
COMBINATION THERAPY IN HUMAN ES CELL TRANSPLANTATION AFTER NEONATAL STROKE
Ling Wei, Dr.
Emory University, 1599 Clifton Road, 4th Floor, Atlanta, Ga 30322
Grant 5R01NS058710-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Ischemic neonatal stroke is a common CNS disorder, yet no effective treatment is currently available. Embryonic stem (ES) cell transplantation after ischemic stroke has been tested extensively as a possible repair therapy in adult animals, however, little investigation has been done to evaluate ES cell transplantation in neonatal ischemic strokes. In the proposed studies, transplantation therapy using human ES cells (hESCs) will be tested in a rat neonatal ischemia model targeting the whisker-barrel cortex. We will address three key issues in hESC transplantation 1) to promote survival of hESC- derived neural cells after transplantation into the harsh ischemic environment; 2) to promote endogenous regenerative responses (angiogenesis and neurogenesis) after stroke and hESC transplantation, and to understand regulatory signals in these responses; 3) to guide and improve synaptogenesis, neurovascular remodeling and functional recovery in the whisker-barrel pathway after hESC transplantation. Based on our previous investigations on mouse ES cells and preliminary studies on hESCs, neurally differentiated hESCs will be subjected to hypoxic preconditioning (HP) before transplantation in order to increase their tolerance to the destructive environment in the ischemic brain. Expression of the essential regulatory genes for cell survival and regenerative responses will be assessed after transplantation. Synaptic transmission represents a fundamental neuronal activity. We will test the hypothesis that HP can promote neurite outgrowth, synaptogenesis and functional activities of hESC-derived neurons in vitro (Aim 1) and in vivo (Aim 2). As a use-dependent rehabilitation strategy, intensified afferent signals induced by whisker stimulation will be tested for the ability to promote and guide transplanted hESC-derived cells and endogenous mechanisms in rebuilding better organized and more functional neurovascular architecture of the whisker-barrel cortex and thalamocortical connections (Aim 3). Cellular and molecular biological, immunohistochemical and electrophysiological techniques will be applied to acquire a comprehensive understanding of the mechanisms and functional benefits of human stem cell therapy boosted by HP and an enriched environment. Results from these experiments will likely improve the efficacy and efficiency of hESC transplantation in ischemic neonates.Transplantation therapy using human ES cells (hESCs) will be tested in a rat neonatal ischemia model targeting the whisker-barrel cortex. We will address three key issues in hESC transplantation 1) to promote survival of hESC-derived neural cells after transplantation; 2) to promote endogenous regenerative responses; 3) to guide and improve the repair process and functional recovery in the whisker-barrel pathway after hESC transplantation
Keywords: 0-6 weeks old; 21+ years old; Acquired brain injury; Address; Adult; Animals; Apoplexy; Apoptosis; Apoptosis Pathway; Architecture; Biological; Brain; Brain Injuries; CNS Diseases; CNS disorder; Cell Communication and Signaling; Cell Culture Techniques; Cell Death, Programmed; Cell Signaling; Cell Survival; Cell Transplantation; Cell Viability; Cells; Central Nervous System Diseases; Central Nervous System Disorders; Cerebral Ischemia; Cerebral Palsy; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Child Development Disorders, Specific; Combined Modality Therapy; Common Rat Strains; Developmental Delay; Developmental Delay Disorders; Dysfunction; ES cell; Embryo; Embryonic; Embryonic Stem Cell Transplantation; Encephalon; Encephalons; Engineering / Architecture; Environment; Epilepsy; Epileptic Seizures; Epileptics; Functional disorder; GFAC; Genes, Regulator; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Human, Adult; Hypoxia; Hypoxic; Impairment; In Vitro; Infant; Infant, Newborn; Intracellular Communication and Signaling; Investigation; Investigators; Ischemia; Ischemic Stroke; Mammals, Mice; Mammals, Rats; Methods; Methods and Techniques; Methods, Other; Mice; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mortality; Mortality Vital Statistics; Motor; Multimodal Therapy; Multimodal Treatment; Multimodality Treatment; Murine; Mus; Neonatal; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neural Growth; Neural Transmission; Neurites; Neurocyte; Neuronal Growth; Neurons; Newborn Infant; Newborns; Occlusion, Middle Cerebral Artery; Oxygen Deficiency; Pathway interactions; Perinatal; Peripheral; Physiatric Procedure; Physical Health Services / Rehabilitation; Physical Medicine Procedure; Physical Therapeutics; Physical Therapy Procedure; Physical Therapy Techniques; Physical therapy; Physiopathology; Physiotherapy; Physiotherapy (Techniques); Physiotherapy Procedure; Plastics; Process; Progenitor Cell Transplantation; Rat; Rattus; Recovery of Function; Regulator Genes; Rehabilitation; Rehabilitation therapy; Rehabilitation, Medical; Research; Research Personnel; Researchers; Seizure Disorder; Sensory; Signal Transduction; Signal Transduction Systems; Signaling; Stem Cell Transplantation; Stem Cell Transplantation, Embryonic; Stem cell transplant; Stroke; Structure; Synaptic Transmission; Techniques; Testing; Transcriptional Regulatory Elements; Transplantation; Vascular Accident, Brain; Vibrissae; Whiskers; adult animal; adult human (21+); angiogenesis; barrel cortex; base; biological signal transduction; brain attack; brain damage; brain lesion (from injury); cerebral vascular accident; clinical significance; clinically significant; combination therapy; combined modality treatment; combined treatment; effective therapy; embryonic stem cell; epilepsia; epileptiform; epileptogenic; experiment; experimental research; experimental study; functional outcomes; functional recovery; hESC; human ES cell; human ESC; human disease; human embryonic stem cell; human embryonic stem cell transplantation; human stem cells; improved; in vivo; mature animal; multimodality therapy; neonate; neurogenesis; neuronal; newborn human (0-6 weeks); pathophysiology; pathway; preconditioning; regenerative; regulatory gene; rehab strategy; rehabilitation strategy; rehabilitative; repair; repaired; research study; response; stem; stem cell of embryonic origin; stem cell therapy; stroke; synapse formation; synaptogenesis; trans acting element; transplant
Project start date: 2009-05-15
Project end date: 2013-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: PA-07-070
5R01NS058710-02 (2010): $276210
3R01NS058710-01A1S1 (2009): $183749
ANGIOGENESIS, FUNCTIONAL RECOVERY AND TNF-ALPHA AFTER STROKE
Ling Wei, Dr.
Emory University, 1599 Clifton Road, 4th Floor, Atlanta, Ga 30322
Abstract: In addition to cell protection, promoting post-ischemic angiogenesis and functional recovery has emerged as a potential approach for the treatment of stroke. Tumor necrosis factor receptor- alpha( (TNF-alpha) and nuclear factor kappa B (NF-(B) play critical roles in many pathological and physiological events including blocking apoptosis and promoting angiogenesis. These two actions of the TNF-(-NF-(B cascade, however, have not been well defined in the ischemic brain. Based on previous and preliminary experiments, we propose to test the hypothesis that the TNF-(-NF-(B pathway-mediated anti-apoptotic effect and angiogenesis promote neurovascular remodeling and functional recovery after a small focal ischemia in the barrel cortex. This unique stroke model to be tested in wild type mice and gene-knockout mice lacking TNF-( receptor TNFR1 (p55), TNFR2 (p75), or NF- kappa B p50 will allow us to examine the TNF-(-NF-(B cascade in the context of pathological and functional changes in the well-defined sensory-motor cortex of the whisker-barrel pathway selectively damaged by the clinically important small stroke. Aim 1. Anti-apoptotic effects of the TNF-(-NF-(B cascade after barrel cortex stroke. We hypothesize that the TNF-(-NF-(B pathway is protective against ischemia-induced apoptosis in neurons and vascular endothelial cells. The effects of selectively eliminating and changing TNFR1, TNFR2, and NF-(B signals on apoptosis will be evaluated after the focal ischemia. Aim 2. Angiogenesis stimulated by the TNF-(-NF-(B cascade after barrel cortex stroke. We will examine the possibility that the TNF-(-NF-(B pathway is involved in increasing angiogenic signals such as vascular endothelial growth factor (VEGF) and angiopoietins that promote angiogenesis after ischemia. We will also test the hypothesis that negative consequences such as carcinogenesis can be averted by modulating angiogenic activity. Aim 3. Functional recovery promoted by the TNF-(-NF-(B cascade after barrel cortex stroke. It is expected that TNF-(-NF-(B -cascade-induced cell survival and angiogenesis promote neurovascular plasticity and long-term functional recovery after the barrel cortex stroke. The cause-effect relationship between these events will be evaluated in wild type and gene-knockout mice by blocking and stimulating the signals identified in Aim 1 and 2. This investigation aims to elucidate the relationship between the TNF-(-NF-(B cascade, apoptosis, and angiogenesis, and functional recovery after a small ischemic stroke that represents 38% of clinical cases. Results from this study are expected to provide novel strategies for promoting functional restoration after focal ischemic stroke
Keywords: No Project Terms available
Project start date: 2004-07-01
Project end date: 2011-03-31
Budget start date: 1-SEP-2008
Budget end date: 31-MAR-2011
7R01NS045810-06 (2008): $0
5R01NS045810-03 (2006): $263753
5R01NS045810-02 (2005): $270100
1R01NS045810-01A1 (2004): $270100
FUNCTION RESTORATION BY ES CELL IMPLANT AFTER ISCHEMIA
Ling Wei, Associate Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 5R01NS045155-04 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Abstract: Embryonic stem (ES) cells can survive and differentiate after transplantation into the adult brain and can potentially be used to promote repair and restore function in the damaged brain. This proposal will explore the possible role of bcl-2 overexpression in enhancing the survival and regenerative potential of ES cells transplanted into rats following barrel cortex ischemia. This system provides a unique model for assessing ES cell effects on angiogenesis and whisker-barrel architecture and function. Specific Aim 1 will compare the effects of bcl-2 over-expression on survival and differentiation of ES cells transplanted into the ischemic barrel cortex. The optimal number of ES cells with and without bcl-2 overexpression to achieve the best survival and differentiation will be determined. Specific Aim 2 will examine whether the improved survival and increased differentiation achieved in Aim 1 will result in greater regenerating potential as demonstrated by morphological (neuronal connections, synapse formation, enhanced angiogenesis) and functional (regional cerebral blood flow, whisker activity-induced optical signals, glucose metabolism, electrical activities) criteria. Specific Aim 3 will explore whether the best strategy for regeneration achieved in Specific Aims 1 and 2 can be further improved by preferential afferent whisker input to the injured barrel cortex. This proposal aims to advance ES cell transplantation strategies beyond the current approaches in an attempt to maximize the regenerating potential.
Keywords: BCL2 gene /protein, embryonic stem cell, ischemia, stem cell transplantation, angiogenesis, apoptosis, cell differentiation, gene expression, nervous system regeneration, vibrissae, autoradiography, histology, immunocytochemistry, laboratory rat, terminal nick end labeling, tissue /cell culture, western blotting
Project start date: 2003-05-15
Project end date: 2008-04-30
5R01NS045155-04 (2006): $304741
5R01NS045155-03 (2005): $312075
5R01NS045155-02 (2004): $312075
Sponsored Links Excellgen http://Excellgen.com
1R01NS045155-01 (2003): $312075
TRANSPLANTATION OF PRE-CONDITIONED BONE MARROW MESENCHYMAL STEM CELLS AFTER ISCHE
Ling Wei, Dr.
Emory University, 1599 Clifton Road, 4th Floor, Atlanta, Ga 30322
Grant 1R01NS062097-01A2 from National Institute Of Neurological Disorders And Stroke
Abstract: Although stem cell transplantation after ischemic stroke has been extensively tested as a possible therapy in adult animals, little research has been done to evaluate stem cell transplantation in neonates. Among the different types of stem cells, bone marrow mesenchymal stem cells (BMSCs) are unique in their potential for multipotentcy and their autograft capability. BMSCs are capable of passing through the blood brain barrer and homing to the ischemic region. The low survival rate of transplanted BMSCs, or stem cells in general, however, has significantly hampered their effectiveness and application in stroke therapy. Making use of our unique barrel cortex ischemic stroke model in the neonate, we will pursue novel approaches to improve both the viability and regenerative capacity of BMSCs. Specific Aim 1 will test the hypothesis that transplantation of BMSCs pre-treated with hypoxic preconditioning (HP) will result in significantly greater functional benefits in the repair of the ischemia- damaged cortex than non-treated BMSCs. Further improvement of functional benefits will be achieved through an enriched environment of target specific physical therapy following BMSC transplantation. Specific Aim 2 will examine the hypothesis that HP-pretreatment of BMSCs significantly enhances their survival after transplantation into the neonatal ischemic brain. The extent of cell death and neural differentiation of BMSCs that home to the ischemic cortex will be compared at 1 to 30 days after transplantation. Specific Aim 3 will examine the effect of transplanted BMSCs on angiogenesis in the post-ischemic brain. We will specifically test the novel hypothesis that HP-increased VEGF expression in BMSCs is a potent stimulator of endogenous angiogenesis, neurogenesis and therefore is effective in the treatment of ischemic stroke. Recovery of local cerebral blood flow (LCBF) and barrel functions after BMSC treatment will be correlated with both angiogenesis and morphological changes. We expect that this novel therapeutic intervention combining 1) administation of HP-BMSCs with 2) an enriched environment, will result in synergistic beneficial effects; if so, this strategy will likely improve the efficacy and efficiency of BMSC transplantation therapy in the treatment of stroke in adults as well as in neonates. A combination strategy will be tested to improve the cell survival quality and regenerative capacities of transplanted bone marrow mesenchymal stem cells (BMSCs) after rat neonatal ischemic stroke. We will address three key issues in BMSC transplantation 1) to promote survival of BMSCs after transplantation; 2) to promote endogenous regenerative responses; 3) to guide and improve the repair process and functional recovery in the whisker-barrel pathway after BMSC transplantation
Keywords: 21+ years old; Address; Adult; Angiogenic Factor; Animals; Antibodies; Apoplexy; Assay; Autograft; Autologous Transplantation; Autotransplant; Behavior; Bioassay; Biologic Assays; Biological Assay; Blood; Blood - brain barrier anatomy; Blood-Brain Barrier; Blotting, Western; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplant; Bone Marrow Transplantation; Brain; Brain region; CNS Diseases; CNS disorder; Cardiovascular Surgical Procedures; Cell Communication and Signaling; Cell Death; Cell Signaling; Cell Survival; Cell Viability; Cells; Central Nervous System Diseases; Central Nervous System Disorders; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Circulation; Cerebrovascular Stroke; Cerebrovascular accident; Chest; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Common Rat Strains; Data; ELISA; Editorial; Editorial (PT); Editorial Comment; Editorial Comment (PT); Editorial [Publication Type]; Effectiveness; Encephalon; Encephalons; Environment; Enzyme-Linked Immunosorbent Assay; Ethical Issues; Exhibits; Exposure to; Factor, Angiogenesis; Future; Goals; Graft Rejection; Graft Survival; Grafting, Bone Marrow; Grant; Hemato-Encephalic Barrier; Home; Home environment; Homing; Human, Adult; Hypoxia; Hypoxic; In Vitro; Intracellular Communication and Signaling; Investigation; Investigators; Ischemia; Ischemic Stroke; Issues, Ethical; Journals; MSC transplantation; Magazine; Mammals, Rats; Marrow Transplantation; Mesenchymal Progenitor Cell; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modeling; Mortality; Mortality Vital Statistics; Mother Cells; Neonatal; Nervous; Nervous System, Brain; Neural Growth; Neurologic; Neurological; Neuronal Growth; Outcome; Oxygen Deficiency; Paper; Pathway interactions; Physiatric Procedure; Physical Medicine Procedure; Physical Therapeutics; Physical Therapy Procedure; Physical Therapy Techniques; Physical therapy; Physiotherapy; Physiotherapy (Techniques); Physiotherapy Procedure; Process; Progenitor Cell Transplantation; Progenitor Cells; Published Comment; Publishing; Rat; Rattus; Recovery; Recovery of Function; Research; Research Personnel; Researchers; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Sensorimotor functions; Signal Transduction; Signal Transduction Systems; Signaling; Staining method; Stainings; Stains; Stem Cell Transplantation; Stem cell transplant; Stem cells; Stroke; Survival Rate; Testing; Therapeutic; Thorace; Thoracic; Thorax; Transplant Rejection; Transplantation; Transplantation Rejection; Transplantation, Autologous; VEGFs; Vascular Accident, Brain; Vascular Endothelial Growth Factors; Vascularization; Vegf; Vibrissae; Viewpoint; Viewpoint (PT); Western Blotting; Western Blottings; Western Immunoblotting; Whiskers; Work; Wound Healing; Wound Repair; Writing; adult animal; adult human (21+); angiogenesis; barrel cortex; biological signal transduction; brain attack; cardiovascular surgery; cell type; cerebral blood flow; cerebral circulation; cerebral vascular accident; cerebrocirculation; editorial; effective therapy; function improvement; functional improvement; functional recovery; improved; in vivo; mature animal; necrocytosis; neonatal human; neonate; neural; neurogenesis; new approaches; novel; novel approaches; novel strategies; novel strategy; novel therapeutic intervention; optic imaging; optical imaging; pathway; preconditioning; protein blotting; public health relevance; regenerative; relating to nervous system; repair; repaired; response; stroke; stroke therapy; tissue repair; transplant
Relevance: A combination strategy will be tested to improve the cell survival quality and regenerative capacities of transplanted bone marrow mesenchymal stem cells (BMSCs) after rat neonatal ischemic stroke. We will address three key issues in BMSC transplantation: 1) to promote survival of BMSCs after transplantation; 2) to promote endogenous regenerative responses; 3) to guide and improve the repair process and functional recovery in the whisker-barrel pathway after BMSC transplantation
Project start date: 2010-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-303
1R01NS062097-01A2 (2010): $339063
Angiogenesis, Functional Recovery And TNF-alpha After Stroke
Ling Wei, Associate Professor
Medical University Of South Carolina 171 Ashley Ave Charleston, Sc 29425
Grant 5R01NS045810-04 from National Institute Of Neurological Disorders And Stroke IRG: ZRG1
Project start date: 2004-07-01
Project end date: 2009-03-31
5R01NS045810-04 (2007): $256104