Alpert Medical School Professor of Neurosurgery, Conrad Johanson, investigates molecular and physiologic aspects of transporter mechanisms at the blood-brain-cerebrospinal fluid (CSF) interfaces that actively create an optimal chemical environment for neuronal functioning. In brain diseases and fluid disorders, pharmacologic remedies are needed to correct distortions in choroid plexus-CSF neurochemistry, in order to overcome cognitive deficits and other neural dysfunctions. Research goal: To restore CSF biochemical composition (homeostasis) and fluid dynamics disrupted by central nervous system pathology. Preserving a functional CSF circulation throughout aging helps to maintain cerebral metabolism, neurotransmission and sound cognition.
Neuropeptide hormones, growth factors and neurotrophic agents, secreted by choroid plexus into cerebrospinal fluid (CSF), play a key role in regulating the neuronal fluid environment: its pressure, volume and composition. Principal Investigator Conrad Johanson has received multiple R01 grants from NIH to study these peptide-mediated regulatory processes. Such peptide/protein modulators in CSF play a key role in driving fetal brain development, by regulating neurogenesis and gliogenesis in the subventricular zone. They also mediate homeostatic control of brain water content, CSF formation rate, and blood-brain barrier permeability in healthy young adults. The CSF Laboratory also analyzes these homeostatic processes in late life when the CNS is stressed by ischemia, trauma, hyperthermia and inflammation. Overall, these peptide/protein regulators in choroid plexus-CSF are up- or down-regulated in order to facilitate brain adjustments to the stressful stimuli encountered in disease or injury.
The Johanson laboratory and colleagues study how the immature, healthy adult and aging central nervous systems react to the stressors of arterial hypertension, reduced blood flow and cerebrospinal fluid formation, elevated intracranial pressure, traumatic brain injury, dehydration, and hyperthermia. The choroid plexus-cerebrospinal fluid (CSF) nexus has a pivotal role in regulating the composition and volume of the brain extracellular fluid, i.e., the microenvironment of neurons. His research team delineates mechanisms of CSF homeostasis and how these transport and distributional phenomena are altered in various pathological states: forebrain ischemia, hydrocephalus, pseudotumor cerebri, hyperthermia, and Alzheimer's disease. The operative working hypothesis is that perturbations and dwindling of the CSF dynamics (reduced CSF turnover) lead to or exacerbate dementia states. Reduced clearance of the beta-amyloid peptide from the CNS, for example, due to attenuated CSF formation and reabsorption, can cause neurotoxicity and destabilize brain metabolism and blood flow.
Models of rats and transgenic mice are being used to provide insight on how fluid balance mechanisms and solute transport at the blood-CSF barrier (choroidal epithelium) and ependyma (brain-CSF boundary) are integrated with corresponding phenomena at the blood-brain barrier interface (cerebral endothelium and astrocytes). The translational goals are to develop agents and regimens that will repair/strengthen the regulatory 'barrier cells' in the choroid plexuses and in the neurovascular unit: endothelial cells, astroglia, pericytes and neurons. By therapeutically stabilizing the choroid plexus and cerebral microvessels in aging and early disease states, e.g., mild cognitive deficit and normal pressure hydrocephalus, it should be feasible eventually to extend neuroprotection and neuroregeneration to the latest periods of the human lifespan.
National Institutes of Health (NIH):
Research Career Development Award, National Institute of Neurological and Communicative Disorders and Stroke (NINDS), 1977-1982
Ontogeny of Homeostatic Transport in Choroid Plexus, NINDS R01 Research Grant, C.E. Johanson, Principal Investigator, 1977-1980
Maturation of CSF Secretory Mechanisms, NINDS R01 Research Grant, C.E. Johanson, Principal Investigator, 1980-1983
Acid-Base Transporters and pH in the Immature CNS, NINDS R01 Research Grant, C.E. Johanson, Principal Investigator, 1983-1986
Development of Choroid Plexus-CSF Transport Systems, NIH NINCDS RO1 Research Grant, C.E. Johanson, Principal Investigator, 1989-1995
Choroid Plexus, Growth Factors, Aging and Injury. NIH NINDS RO1 Research Grant, C.E. Johanson, Principal Investigator, 1995-1999
Peptide Regulation of the Choroid Plexus-CSF System. NIH NINDS RO1, C.E. Johanson, Principal Investigator, 1999-2004
Age-Related Decrease in A-Beta Peptide Clearance Pathways: CSF and BBB, C.E. Johanson, Principal Investigator, NIH NIA R01 Research Grant, 2006-2010.
Research Training in Pharmacological Sciences, NIH Training Grant, research supervisor, 1974-1984
Neuropharmacology and Neurochemistry Program Project, research instructor, 1973-1975
Training Grant for Post-Clinical Anesthesia Training, National Institutes of Health, research advisor, 1980-1985
Pathophysiological Responses to Injury, NIH, National Institute of General Medical Sciences, Institutional Postdoctoral NRSA (T32) M. Epstein, Principal Investigator; C.E. Johanson, Co-Principal Investigator, 1990-1992
Trauma, Sepsis and Inflammation National Institute of General Medical Sciences Trauma Training Grant, I. Chaudry, Principal Investigator, C. Johanson, research supervisor, 1999-2002
Trauma and Inflammation Research Training Grant, National Institute of General Medical Sciences Trauma Training Grant, J. Albina, Principal Investigator, C. Johanson, research supervisor, 2004-2014
Alzheimer's Disease Clinical Center, Neuropathology Core, National Institute on Aging, E. Stopa., Principal Investigator and C. Johanson, Co-investigator, pending.
Agrin, Amyloid and Alzheimer's Disease, Veterans Administration, C. Johanson, Principal Investigator and E. Stopa, co-investigator, pending.
Apolipoprotein E, Amyloid-beta and Blood-Brain Barrier Permeability, K08, National Institutes of Health, J. Donahue, Principal Investigator, and C. Johanson, mentor, 2006-9
National Science Foundation:
Multi-User Equipment Grant, National Science Foundation, 1979-1980
Private Foundations:
Biochemical Control of CSF Production, March of Dimes Foundation, M. Epstein and C. Johanson, Co- Principal Investigator, 1985-1988
Effect of Phenytoin on the Transport and Distribution of Sodium and Potassium between Various Compartments in the Central Nervous System, Epilepsy Foundation of America, C. Johanson, Principal Investigator, 1975-1976
Microdialysis of Cerebrospinal Fluid from the Cisterna Magna. Grass Foundation, C.E. Johanson, Principal Investigator, 1990-1993
Serotonin Effects on Chloride Transport by Choroid Plexus, Grass Foundation, C.E. Johanson, Principal Investigator, 1994
Cystatin C and TUNEL Immunostaining in Spinal Cord in Amyotrophic Lateral Sclerosis, George Robinson Foundation, C.E. Johanson, Principal Investigator, 1996-1997
Growth-factor Induced Hydrocephalus in a Transgenic Alzheimer Mouse Model, Alzheimer's Association, C. Johanson and E. Stopa, co-principal investigators, 2004-2007
Biomarkers for Drug Targeting in Alzheimer's Disease, American Health Assistance Foundation, A. Baird, Principal Investigator, and C. Johanson, Co- Principal Investigator, pending.
Corporations:
Minimally-Invasive and Metabolic Models of Hydrocephalus, Medtronic Neurologic Technologies, C. Johanson and J. Duncan, co-principal investigators, 2006-2009.
Local Funding Sources:
Protection of the pH of the Extracellular Fluid of the Brain during Systemic Metabolic and Respiratory Acidosis: The Role of the Choroid Plexus, C. Johanson, Principal Investigator, Dean's Research Fund, University of Utah, 1976-1977
Physiological Characteristics of the Cerebrospinal Fluid Secretory Process, C. Johanson, Principal Investigator, Dean's Research Fund, University of Utah, 1974-1975
Immunohistochemical Analyses of ALS Brains, Brown University UTRA collaborative study with Jinn-Wien Teng, 1998.
Invited Presentations, by Prof. Johanson (last 5 years)
Department of Neurosurgery, Barrow Neurological Institute, ‘Definition and classification of hydrocephalus’, Phoenix, AZ, January 2010
Universidad Austral de Chile, Institute of Anatomy, Histology and Pathology, Lectures on ‘Adult normal pressure hydrocephalus: An intermediate state between aging and Alzheimer’s disease?’ and ‘Neuropeptides, Na-K-Cl co-transport and choroid epithelial ‘dark’ cells: Impact on CSF and hydrocephalus’, Valdivia, Chile, January 2010
7th Congress of the Global College of Neuroprotection and Neuroregeneration, 'Disruption of the choroid plexus-CSF-ependymal wall nexus in CNS injury and aging models: Rescue by intracerebroventricular peptides' , Stockholm, Sweden, February 2010
ATP/IFSTP 2010 Joint Session/ Toxicology/Neuropathology, 'Fluid homeostasis and protection of the brain by CSF-bordering cells: Role of the choroid plexus, ependyma and circumventricular organs', Chicago, IL June 2010
VIII Global College of Neuroprotection and Neuroregeneration, 'Altered choroid plexus-CSF function in aging and brain injury: How is it related to neurodegeneration and cognition?' Amman, Jordan, April 2011
IXth Congress of the Global College of Neuroprotection and Neuroregeneration,' Augurin: A choroid plexus-CSF secreted peptide derived from the Ecrg4 gene with a putative role in regulating periventricular neurogenesis following traumatic brain injury', Xi’an, China, May 2012
Department of Neurosurgery, Grand Rounds lecture, ‘Experimental modeling of NPH vs. aging and Alzheimer's disease’, University of Louisville Medical School, Louisville, KY, June 2012
CSF and Neurotrauma Symposium, ‘Putative neuroendocrine regulation of intracranial pressure: Implications for the intracranial hypertension of spaceflight’ & ‘Therapeutic attempts to modulate the effects of ependymal denudation and subcommissural organ impairment and modulate trophic factor delivery in hydrocephalus’, University of Birmingham, Edgbaston, United Kingdom, July 2012
Universidad Austral de Chile, Institute of Anatomy, Histology and Pathology, ‘Altered choroid plexus, CSF and ependymal wall in aging and brain injury: Relations to neurogenesis, regeneration and cognition’, Valdivia, Chile, March 2012
Animal Models in Hydrocephalus Research, ‘Augurin, a choroid plexus-CSF hormone for restoring brain homeostasis after injury: Implications for hydrocephalus’, Satellite conference at the SRHSB annual meeting, York, England, July 2012
Smart Medical Systems and Technology: Unraveling VIIP Etiology (NASA)- An Exploratory Symposium- ‘Neuropeptide regulation of choroid plexus-CSF dynamics: Emerging role for central atrial natriuretic peptide’, Houston, TX, February 2014
VII Annual Conference of International Association of Neurorestoratology, ‘Agrin expression level in the blood-brain barrier affects the content of beta-amyloid in the brain of transgenic mice’, Mumbai, India, March 2014
Department of Neurology, Rhode Island Hospital, 'Breakdown of blood-brain and blood-CSF barriers disrupts the CNS in aging and Alzheimer's: Pathophysiology, diagnostics and repair potential', Providence, RI, November, 2014
Dallas Independent School District, Neuroscience presentation on choroid plexus to high school students: 'Redistribution of brain and cerebrospinal fluids in astronauts subjected to microgravity in the International Space Station', Dallas, TX, 2015.
