Research Interests:
Dr. Gibson's research is focused on murine models of inborn errors of metabolism. A primary objective is an expanded understanding of pathophysiology, in order to develop improved preclinical approaches to treatment. In addition to pathophysiology, the laboratory utilizes hepatocyte engraftment/repopulation as a mechanism to treat genetic disease, especially neurometabolic disorders, in conjunction with Dr. Stephen Strom in Pathology. Another focus is understanding the pharmacological mechanisms for metabolism of gamma-hydroxybutyric acid (GHB), as well as its precursors gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD). These compounds represent the so-called "club drugs" gaining increasing notoriety.
A prime focus in the Gibson lab are studies on a murine knockout of succinate semialdehyde dehydrogenase, the second of two enzymes involved in GABA metabolism. These mice manifest significant elevations of GABA and GHB, and succumb to lethal seizure activity in week 3-4 of life in the absence of pharmacotherapeutics. SSADH-deficient mice serve as a model for juvenile myoclonic epilepsy, and transition from absence to generalized tonic-clonic convulsions in a 10 day window. The mechanism of this transition is under investigation in the laboratory. In addition, murine models of specific cholesterol biosynthetic and biotin-dependent metabolic defects are under investigation
Selected Publications:
Jansen EE, Verhoeven NM, Jakobs C, Schulze A, Senephansiri H, Gupta M, Snead OC, Gibson KM. Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency. Biochim Biophys Acta. 2006 Feb 10;
Struys EA, Verhoeven NM, Jansen EE, Ten Brink HJ, Gupta M, Burlingame TG, Quang LS, Maher T, Rinaldo P, Snead OC, Goodwin AK, Weerts EM, Brown PR, Murphy TC, Picklo MJ, Jakobs C, Gibson KM. Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidence for d-2-hydroxyglutarate transhydrogenase.
Metabolism. 2006 Mar;55(3):353-8.
Wu Y, Buzzi A, Frantseva M, Velazquez JP, Cortez M, Liu C, Shen L, Gibson KM, Snead OC 3rd. Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms. Ann Neurol. 2006 Jan;59(1):42-52.
Snead OC 3rd, Gibson KM. Gamma-hydroxybutyric acid. N Engl J Med. 2005 Jun 30;352(26):2721-32. Review. No abstract available. Erratum in: N Engl J Med. 2006 Feb 2;354(5):537.
Weerts EM, Goodwin AK, Griffiths RR, Brown PR, Froestl W, Jakobs C, Gibson KM. Spontaneous and precipitated withdrawal after chronic intragastric administration of gamma-hydroxybutyrate (GHB) in baboons. Psychopharmacology (Berl). 2005 May;179(3):678-87. Epub 2005 Jan 12.
Cortez MA, Wu Y, Gibson KM, Snead OC 3rd. Absence seizures in succinic semialdehyde dehydrogenase deficient mice: a model of juvenile absence epilepsy.
Pharmacol Biochem Behav. 2004 Nov;79(3):547-53.
