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Joseph F. Clark, PhD

Title

Associate Professor

Appointment

Associate Professor

Email

joseph.clark@uc.edu

Phone

513-558-7985

Fax

513-558-7009

Bio

Dr. Clark obtained his Ph.D. in physiology from Michigan State University in 1990. He spent 18 months in the University of Paris (Sud) doing a post doc in the department of Biophysics and went to the Department of Biochemistry in Oxford University. There he progressed from post doc to group leader. In 2000 he moved from Oxford to Cincinnati.
Dr Clark studies the biochemical mechanisms of cerebral vascular and cardiovascular diseases. He has over 40 publications in refereed journals is co-inventor on 10 invention disclosures, provisional patents or patents, and has authored or co-authored 2 texts.

Research

CAUSES OF CEREBRAL VASOSPASM. Vasospasm is a frequent cause of delayed ischemic stroke in subarachnoid hemorrhage (SAH) patients. We have isolated the vasoactive molecules found in the cerebral spinal fluid of subarachnoid hemorrhage patients that appear to cause cerebral vasospasm. The long-term objective of this research is to prove that these are the molecule(s) that cause cerebral vasospasm following SAH. It is proposed that oxidation of bilirubin following SAH produces compounds that inhibit protein phosphatases, and that this inhibition causes the vasoconstriction and vascular proliferation seen in patients with vasospasm. We have identified candidate molecules that are peroxidized fragments of bilirubin that produce vasoconstriction of vascular smooth muscle.
NON TECHNICAL SUMMARY. We have identified the molecules which may cause about 10% of all strokes. This has led to several patents designed to diagnose and treat this type of stoke by detecting and blocking these molecules.

PREGNANCY INDUCED HYPERTENSION. We have data showing that a substance in the blood of pregnant women causes a significant, but reversible vasoconstriction and stimulation of respiration of porcine vascular smooth muscle in vitro and that this stimulation is greater in pre-eclamptic patients. The cause of this stimulation appears to be due to vasoactive molecules produced in the placentas of these patients. Recently, we have developed an extraction procedure for analyzing the vasoactive molecules in serum/blood and placental extracts and we are working on purifying these molecules and determining how they cause pre-eclampsia.
NON TECHNICAL SUMMARY. Stroke is the number one cause of maternal mortality in the USA and we are in the process of purifying the molecules that may cause this stroke. After we identify the molecules that cause the stroke we will design ways to predict and prevent this from happening to pregnant women.

CREATINE AND BRAIN METABOLISM of CREATINE
Recently we reported on a 6 year old boy who had a unique creatine deficiency of the brain, which was diagnosed by proton MR Spectroscopy. Upon further analysis, we found that he has a nonsense mutation in the X-linked Creatine Transporter gene (CT1;SLC6A8) which resulted in a truncated Cr Transporter protein. Despite a growing body of knowledge about the Cr/PCr/CK system in the brain, there is no definitive method for diagnosing or treating patients who lack the creatine transporter or who have metabolic dysfunctions associated with brain energy metabolism. Currently we are following the pathogenesis and progress of the disease in the patients and carriers as well as determining the prevalence of the disease. Also, we are developing a mouse model of this disease such that the efficacy of new treatment paradigms, drugs and other therapies, can be tested.

NON-TECHNICAL SUMMARY. There are approximately a quarter of a million people in the USA who are mentally retarded where the cause of this mental retardation is unknown. We have discovered a new disease, which may be the cause of this mental retardation. We are developing ways to diagnose and treat this disease. We believe that if caught early enough, we could treat these people and make them normal and productive people.

STROKE AND BLOOD CLOT.

Apolipoprotein E (Apo E), and its respective isoforms, has been linked to outcome and survival following acute central nervous system injury. The effectiveness of intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke is enhanced in patients who have an Apo E2 genotype. The ability of Apo E isoproteins to modulate tPA induced clot lysis is being assessed for its possible role in stroke and stroke therapy. We have found that Apo E isoproteins can modulate tPA induced clot lysis. This modulation of clot lysis is consistent with the observed benefit of the Apo E2 genotype in patients receiving tPA. Our results suggest that Apo E may have an impact on clot dissolution and the effectiveness of thrombolytic therapy and we are currently trying to develop ways to develop better treatments for these patients.

NON-TECHNICAL SUMMARY. We have discovered a way to make current stroke therapy more effective and safer. This is because it may be possible to give a second drug with the drug currently given (tPA) and increase or decrease the effectiveness of tPA. Therefore, we may be able to give less tPA with more potent effect, or even turn off if necessary.

Research Grants and Contracts

Dr Clark currently has multiple grants from the NIH, the American Heart Association as well as smaller grants.

Publications, Most Recent

J.F. Clark, M. Reilly, F. R. Sharp. Oxidation of Bilirubin Produces Compounds that Cause Prolonged Vasospasm of Rat Cerebral Vessels: A Contributor to Subarachnoid Hemorrhage Induced Cerebral Vasospasm. Journal of Cerebral Blood Flow and Metabolism 22;472-478, 2002

J.F. Clark, DA Huri, J. Carrozzella, E. C. Jauch, P Mehta, S. J. Biehle, F. R. Sharp, and J.P. Broderick MD. Isoforms of Apolipoprotein E Can Modulate tPA Induced Clot Lysis In Vitro. Frontiers in Bioscience 7; a163-168, 2002.

A. Lu, R. Ran J.F. Clark, M Reilly, A. Nee and F.R. Sharp. 17-b-Estradiol Induces Heat Shock Proteins in Brain Arteries, and Potentiates Ischemic Heat Shock Protein Induction in Glia and Neurons. Journal of Cerebral Blood Flow and Metabolism. 22;183-195, 2002

G.J. Pyne T.A.D. Cadoux-Hudson, J.F. Clark. Magnesium Protects Against Subarachnoid Haemorrhage Induced Cerebral Vasospasm In Vitro. British Journal of Neurosurgery, 15;409-415 2001.

J.F. Clark, G.J. Pyne, O.J. Choutka, J.A. Carrozzella, J. Khoury, J.P. Broderick, and T.A.D. Cadoux-Hudson. In Vitro Therapy with Dobutamine, Isoprenaline and Sodium Nitroprusside Protects Vascular Smooth Muscle Metabolism from Subarachnoid Hemorrhage Induced Cerebral Vasospasm. Acta Neurochirurgica 143;721-728 2001.

G.J. Pyne, T.A.D. Cadoux-Hudson, and J.F. Clark. Cerebrospinal Fluid from Subarachnoid Haemorrhage Patients Causes Excessive Oxidative Metabolism Compared to Vascular Smooth Muscle Force Generation. Acta Neurochirurgica 143; 59-63, 2001

T.A.D. Cadoux-Hudson, G.J. Pyne, Z. Domingo, and J.F. Clark. The Stimulation, of Vascular Smooth Muscle Oxidative Metabolism by CSF from Subarachnoid Haemorrhage Patients Increases with Fisher and WFNS Grades. Acta Neurochirurgica 143; 65-72, 2001

K.R. Kranc, G.J. Pyne, L. Tao, T.D.W. Claridge, D.A. Harris, T.A.D. Cadoux-Hudson, J.J. Turnbull, C.J. Schofield and J.F. Clark. Oxidative Degradation of Bilirubin Produces Vasoactive Compounds. European Journal of Biochemistry. 267; 7094-7101 2000.

N.F. Thomson, S. Thornton, and J.F. Clark. The Effects of Placental Extracts from Normotensive and Preeclamptic Women on Vasoconstriction and Oxidative Metabolism. American Journal of Obstetrics and Gynacology. 183; 206-210, 2000.

G.J. Pyne, T.A.D. Cadoux-Hudson and J.F. Clark. An Extractable Phosphatase Inhibitor is Present in the CSF of Subarachnoid Hemorrhage Patients with Vasospasm. Biochimica et Biophysica Acta, 1474; 283-290, 2000.

J.F. Clark, G.K. Radda and E.A. Boehm. The Effects of Anti-Hypertensive Therapy on the Structural, Mechanical and Metabolic Properties of the Rat Aorta. Journal of Muscle Research and Cell Motility. 21; 255-267, 2000.

L.M. Brewster, J.F. Clark, G.A. van Montfrans. Is Greater Tissue Activity of Creatine Kinase The Genetic Factor Increasing Hypertension Risk in Black People of Sub-Saharan African Descent? Journal of Hypertension. 18; 1537-1544, 2000.

J.F. Clark, T. Matsumoto and S. Nakayama. Intact Smooth Muscle Metabolism: Its Responses to Cyanide Poisoning and Pyruvate Stimulation. Frontiers in Bioscience 5a; 18-23, 2000.

T.A.D. Cadoux-Hudson, G.J. Pyne, and J.F. Clark. Subarachnoid Haemorrhage Induced Cerebral Vasospasm: A Subcellular Perspective on the Control of Tension. Emerging Therapeutic Targets. 3; 439-452, 1999.

J.F. Clark and K.R. Kranc, The Role of the Mitochondrion in Smooth Muscle Cell Fate Choices of Proliferation Versus Apoptosis During Vascular and Cardiovascular Disease. Emerging Therapeutic Targets. 3; 513-525, 1999.

W.S. Kunz, A.V. Kuznetsov, J.F. Clark, I. Tracey, and C.E. Elger. Metabolic consequences of the cytochrome c oxidase deficiency in brain of copper-deficient Movbr mice. Journal of Neurochemistry. 72; 1580-1585, 1999.

M.C. Bearchell, C.W.G. Redman, G.J. Pyne, T.A.D. Cadoux-Hudson, and J.F. Clark. Vascular Smooth Muscle Oxygen Consumption is Reversibly Stimulated by Sera from Women with Pre-Eclampsia. American Journal of Obstetrics and Gynecology. 179; 1534-1538, 1998.

J.F. Clark. Creatine: A Review of its Nutritional Applications in Sport. Journal of Nutrition, 14; 322-324, 1998.

G.J. Kemp, D.N. Manners, J.F. Clark, M.E. Bastin, and G.K. Radda. Theoretical modelling of some spatial and temporal aspects of the mitochondrion/creatine kinase/myofibril system in muscle. Molecular Cell Biochemistry. 184; 249-289, 1998.

J.F. Clark, A.V. Kuznetsov, and G.K. Radda. ADP Regenerating Enzyme Systems in the Mitochondria of the Guinea Pig Myometrium and Heart. American Journal of Physiology, Cell Physiology. 41; C399-C404, 1997.

S. Nakayama, S. Chihara, J.F. Clark, S.-M. Huang, T. Horiuchi, & T. Tomita. Consequences of metabolic inhibition in smooth muscle isolated from guinea-pig stomach. Journal of Physiology. 505; 229-240, 1997.

J.F. Clark. Creatine and Phosphocreatine: A Review of Their Uses in Exercise and Sport. Invited Review, Journal of Athletic Training. 32;45-51, 1997.

M.L. Field, and J.F. Clark. Inappropriate Ubiquitin Conjugation: A Proposed Mechanism Contributing to Heart Failure. Cardiovascular Research, 33; 8-12, 1997.

E.A. Boehm, G.K. Radda, H. Tomlin, and J.F. Clark. Utilisation of Creatine and its Analogues by Cytosolic and Mitochondrial Creatine Kinase. Biochimica et Biophysica Acta, 1274; 119-128, 1996.

A.V. Kuznetsov, J.F. Clark, K. Winkler and W.S. Kunz. Change in Flux Control Coefficient of Cytochrome C Oxidase in Copper Deficient Mottled Brindled Mice. Journal of Biological Chemistry, 271; 283-288, 1996.

B. Leighton, A. Sanderson, M. Young, G.K. Radda, E. Boehm, and J.F. Clark. Effects of Treatment of Spontaneously Hypertensive Rats with the Angiotensin Converting Enzyme Inhibitor Trandolapril on the Sensitivity of Glucose Metabolism to Insulin in Isolated Incubated Soleus Muscle Preparations. Diabetes, 45; S120-S124, 1996

E. A. Boehm, J. F. Clark, and G. K. Radda. Metabolite Utilization and Possible Compartmentation in Porcine Carotid Artery: A Study Using b-Guanidinopropionic Acid. American Journal of Physiology, 268; C628-C635, 1995.

J.F. Clark, and P.F. Dillon. Phosphocreatine and Creatine Kinase in Energetic Metabolism of the Porcine Carotid Artery. Journal of Vascular Research, 32; 24-30, 1995.

P.F. Dillon, M.K Weberling, S.M. LeTarte, J.F. Clark, P.M. Sears and R.S. Root-Bernstein. Creatine Kinase Increases the Solubility and Enzymatic Activity of Pyruvate Kinase by Means of Diazymatic Coupling. Journal of Biological Physics, 21; 11-23, 1995.

J.F. Clark, G.J. Kemp and G.K. Radda. The Creatine Kinase Equilibrium, Free [ADP] and Myosin ATPase in Vascular Smooth Muscle Cross-Bridges. Journal of Theoretical Biology, 173; 207-211, 1995.

J.F. Clark, Z. Khuchua, A.V. Kuznetsov, L. Vasilyeva, E. Boehm, G.K. Radda and V. Saks. Actions of the Creatine Analogue b-Guanidinopropionic Acid on Rat Heart Mitochondria. Biochemical Journal, 300; 211-216, 1994.

J.F. Clark, A.V. Kuznetsov, Z. Khuchua, V. Veksler, R. Ventura-Clapier, and V.A. Saks. Creatine Kinase Function in Mitochondria Isolated from Gravid and Non-Gravid Guinea-Pig Uteri. FEBS Letters, 347;147-151, 1994.

J.F. Clark. The Creatine Kinase System in Smooth Muscle. Molecular and Cellular Biochemistry, 133/134; 221-232, 1994.

J.F. Clark, Z. Khuchua, A.V. Kuznetsov, E. Boehm and R. Ventura-Clapier. Creatine Kinase Activity Associated with the Contractile Proteins of the Guinea Pig Carotid Artery. Journal of Muscle Research and Cell Motility, 15; 432-439, 1994.

M.L. Field, J.F. Clark, C. Henderson, A-M Seymour, and G.K. Radda. Alterations in the Myocardial Creatine Kinase System During Chronic Anaemic Hypoxia. Cardiovascular Research, 28; 86-91, 1994.

J.F. Clark, Z. Khuchua, A.V. Kuznetsov, V.A. Saks, and R. Ventura-Clapier. The Compartmentation and Role of Creatine Kinase in the Myometrium of the Gestating Guinea Pig Uterus. Journal of Physiology, (London), 466; 553-572, 1993.

J.F. Clark, Z. Khuchua, and R. Ventura-Clapier. Creatine Kinase Binding and Possible Role in Chemically Skinned Guinea Pig Taenia Coli. Biochimica et Biophysica Acta, 1100; 137-145, 1992.

J.F. Clark, G.I. Harris, and P.F. Dillon. Multisite Saturation Transfer Using DANTE and Continuous Wave. Magnetic Resonance In Medicine, 17; 274-278, 1991.

P.F. Dillon and J.F. Clark. The Theory of Diazymes and functional Coupling of Pyruvate Kinase and Creatine Kinase. Journal of Theoretical Biology, 143; 275-284, 1990.