The long-term objective of this research is to develop a cell therapy for the treatment of neurological disorders that are due to dysfunctional astrocytes. Current approaches to cure or manage these diseases by small molecule drugs are limited due to the polygenic and multifactorial nature of the disease. In addition, the blood brain barrier creates a significant hurdle for these drugs to target the diseased cell population. Using a targeted strategy of cell-transplant based therapy, diseases as diverse as lysosomal storage disorders and leukodystrophies, Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig's Disease), and Parkinson's Disease may all be approachable. Unlike small molecule therapeutics, natural proteins and compounds may be expressed at sufficient levels, at appropriate times, and at proper organ location by the transplanted cells to counteract the dysfunctional imbalance of the endogenous diseased cells. This proposal describes development of a human derived astrocyte-restricted precursor (ARP) cell population to meet the long-term objectives stated above. This population of cells has been defined in the CNS of rodents and we intend to build on this knowledge for isolation of the human cellular ortholog. We will first define optimal purification and growth conditions for ARPs using fully defined medium conditions, and then assess the ability of ARPs to differentiate into astrocytes after transplantation into the CNS of an animal model. Successful completion of these studies will form the basis for additional pre-clinical analysis of these cells in a rat model for ALS. In addition to their use as a therapy, Invitrogen and several other pharmaceutical companies have expressed interest in obtaining these cells for drug screening purposes. Another goal of this project is to provide a pure and consistent astrocyte population derived from ARPs to these companies.
Public Health Relevance: Recent data suggest that dysfunctional astrocytes lead to disease progression in Amyotrophic Lateral Sclerosis (ALS; Lou Gerhig's Disease). Development of an astrocyte-restricted precursor cell population may hold promise as a therapy for this disease.
Thesaurus Terms: Als; Amyotrophic Lateral Sclerosis; Animal Model; Animal Models And Related Studies; Antibodies; Antigenic Determinants; Astrocytes; Astrocytus; Astroglia; Astroprotein; Binding Determinants; Blood - Brain Barrier Anatomy; Blood-Brain Barrier; Body Tissues; Cd44; Cd44 Gene; Cns Diseases; Cns Disorder; Cadaver; Cell Communication And Signaling; Cell Line; Cell Lines, Strains; Cell Signaling; Cell Surface Glycoproteins; Cell Therapy; Cell Transplants; Cellline; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Disorders; Common Rat Strains; Conditioned Culture Media; Conditioned Medium; Culture Media; Culture Media, Conditioned; Data; Development; Disease; Disease Progression; Disorder; Drug Evaluation, Preclinical; Drug Formulations; Drug Screening; Drugs; Dysfunction; Effectiveness; Epitopes; Evaluation Studies, Drug, Pre-Clinical; Evaluation Studies, Drug, Preclinical; Expression Profiling; Expression Signature; Formulation; Formulations, Drug; Foundations; Functional Disorder; Gfa-Protein; Gfap; Gehrig's Disease; Gene Expression; Generalized Growth; Genes; Glia; Glial Cells; Glial Fibrillary Acid Protein; Glial Fibrillary Acidic Protein; Glial Intermediate Filament Protein; Goals; Growth; Growth Factor Receptors; Hand; Hemato-Encephalic Barrier; Housekeeping; Housework; Human; Human, General; Idiopathic Parkinson Disease; Immune; In Vitro; Intracellular Communication And Signaling; Knowledge; Kolliker's Reticulum; Lead; Lewy Body Parkinson Disease; Life; Ligands; Location; Lou Gehrig Disease; Mdu3; Mammals, Mice; Mammals, Rats; Mammals, Rodents; Man (Taxonomy); Man, Modern; Marketing; Medication; Membrane Glycoproteins; Methods; Methods And Techniques; Methods, Other; Mice; Moab, Clinical Treatment; Modeling; Molecular Fingerprinting; Molecular Profiling; Monoclonal Antibodies; Mother Cells; Motor Neuron Disease, Amyotrophic Lateral Sclerosis; Murine; Mus; Myelin Basic Proteins; Nature; Nerve Cells; Nerve Unit; Nervous; Nervous System Diseases; Nervous System Physiology; Nervous System, Cns; Neural Cell; Neuraxis; Neurocyte; Neuroglia; Neuroglial Cells; Neurologic Disorders; Neurologic Function; Neurological Disorders; Neurological Function; Neuronal Differentiation; Neurons; Non-Neuronal Cell; Nuclear Antigens; Oligodendrocytes; Oligodendrocytus; Oligodendroglia; Oligodendroglia Cell; Organ; Ortholog; Orthologous Gene; Psa-Ncam; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's Disease; Parkinsons Disease; Pb Element; Pgp1; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Phase; Phenotype; Physiopathology; Population; Preclinical Drug Evaluation; Primary Parkinsonism; Progenitor Cells; Proliferating; Proteins; Proto-Oncogene, Growth Factor Receptor; Radial; Rat; Rattus; Receptor Cell; Receptor Protein; Research; Rodent; Rodentia; Rodentias; Sbir; Sbirs (R43/44); Shivering; Shiverings; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signal Transduction Systems; Signaling; Small Business Innovation Research; Small Business Innovation Research Grant; Source; Stem Cells; Surface Glycoproteins; Techniques; Technology; Therapeutic; Therapy, Cell; Time; Tissue Growth; Tissues; Transplantation; Tubulin; Xenobiotics; Base; Biological Signal Transduction; Cell Behavior; Cell-Based Therapy; Cultured Cell Line; Design; Designing; Disease/Disorder; Drug Discovery; Drug/Agent; Efficacy Testing; Experiment; Experimental Research; Experimental Study; Fetal; Gene Product; Growth Media; Heavy Metal Pb; Heavy Metal Lead; Human Data; Immunocytochemistry; In Vivo; Interest; Leukodystrophy; Magnetic Beads; Meetings; Model Organism; Molecuar Profile; Molecular Signature; Nerve Cement; Nervous System Disorder; Nervous System Function; Nestin; Nestin Protein; Neural; Neurological Disease; Neuronal; Ontogeny; Pathophysiology; Polysialyl Ncam; Polysialyl Neural Cell Adhesion Molecule; Pre-Clinical; Preclinical; Precursor Cell; Progenitor; Public Health Relevance; Receptor; Relating To Nervous System; Research Study; Self-Renewal; Small Molecule; Superparamagnetic Beads; Tool; Transplant
