Department of Metabolic and Endocrine Diseases
University Medical Center Utrecht
Room KC.02.069.1
Lundlaan 6
3584 EA Utrecht
The Netherlands
phone: 088 - 75 553 18
fax: 088 - 75 542 95
e-mail:
L.Klomp@umcutrecht.nl Date and place of birth: 21-01-1967, Apeldoorn
Scientific education
1985-1990:
Medical Biology: Utrecht University, school of medicine; research projects: molecular biology (Dr. P.H. Steenbergh and Prof. Dr. J.S. Sussenbach) and cell biology (Dr. J. Dekker and Prof. Dr. G.J. Strous). Graduated: 02-07-1990
Research experience aug 1990-jan 1994
PhD project at the Utrecht University, school of medicine, department of cell biology; project financially supported by NWO; supervisor Prof. Dr. G.J. Strous
dissertation: 24-01-1995
titled: Structure and Biosynthesis of Human Mucus Glycoproteins; promotor: Prof. Dr. G.J. Strous
jan 1995-june 1997
Postdoctoral research associate, Washington University St. Louis, MO, USA, school of medicine, department of pediatric immunology/rheumatology; supervisor Prof. Dr. J.D. Gitlin
jun-sep 1997
Postdoctoral research associate, Leiden University; Leiden Amsterdam Institute for the Study of Drug Research; supervisors: Dr. E. Biessen, Prof. Dr. T.J. van Berkel
sep 1997-sep 2000
Postdoctoral research associate, UMC Utrecht, department of pediatric gastroenterology; supervisors: Dr. R.H.J. Houwen, Prof. Dr. R. Berger
sep 2000-present
staff member, department of metabolic disorders
Dr. Klomp's research activities during the past decade have focused on the characterization of basic molecular and cellular processes with biomedical relevance. The applicant is particularly interested in the gastrointestinal. Inherited disorders in humans served as paradigms for further research.
The work performed from 1990-1994, under the supervision of Prof. Dr. G.J. Strous, which is described in his doctoral thesis, involved studying the molecular structure of human mucin-type glycoproteins (mucins). These molecules constitute the main structural and functional component of epithelial mucus layers. Changes in mucus composition have been associated with cancer metastasis, cystic fibrosis, gallstone formation and ulcers of the gastrointestinal system. Mucins are extremely large glycoproteins with a very complicated structure, which is essential for their special physico-chemical properties. Through a combination of molecular cloning and biosynthetic studies, the structural components of human gastric and biliary mucins were systematically unraveled and the subsequent steps in the intracellular biosynthesis of these macromolecules were delineated.
Leo Klomp became interested in elucidating the mechanisms of liver copper homeostasis in relation to copper storage disorders during his postdoctoral fellowship in the laboratory of Prof. Dr. J.D. Gitlin in St. Louis (1995-1997). By analyzing the expression of the copper-dependent ferroxidase ceruloplasmin, he was able to explain the predominant neuropathology of patients with aceruloplasminemia, a newly described neurodegenerative disorder. In addition, he cloned two novel human genes encoding ATOX1 and CCS. These are copper chaperone proteins; cytoplasmic proteins necessary for the specific targeting of copper to intracellular target proteins, while keeping the potential toxic metal in a non-reactive form. The functions of these proteins were characterized in yeast and mice; this work resulted in the novel and exciting concept of intracellular metal chaperone function. Together with a PhD student (Diana Klomp; financially supported by NWO grant 902-23-252), the basic mechanisms of cellular copper influx and intracellular distribution are currently further studied, focussing on the putative high-affinity copper transporter CTR1. We have developed polyclonal antisera to human CTR1. Immunofluorescence experiments indicated that CTR1 cycles between a perinuclear intracellular compartment and the plasma membrane. These results indicated that CTR1 function might be regulated by means of influencing the cell surface expression of the transporter. Further experiments indicated that the N-terminal domain of CTR1 is located on the exoplasmic side of the membrane and binds copper and other divalent metals. This domain also interacts with itself in Y2H analyses, suggesting that CTR1 is functional as a multimer. A pilot Y2H library screen using one CTR1 domain revealed a number of interesting candidate interacting proteins, which are currently further studied. We have recently started a collaboration with Dr. C. Wijmenga to investigate the role of Murr1 (the deficient protein in Bedlington terriers affected with copper toxicosis) in the regulation of hepatic copper excretion. Two AIO's (Prim de Bie and Patricia Muller) are working on this project.
During his second postdoctoral fellowship with Dr. R. Houwen (UMC Utrecht), Leo Klomp has focused his efforts on the cell biological characterization of inherited metabolic disorders of the liver. He has made contributions towards positional cloning of the FIC1 gene, which is mutated in patients with some familial forms of progressive cholestasis and Greenland Familial Cholestasis. He has raised antibodies to FIC1, which were initially used to characterize the expression pattern of FIC1. Currently he works on the cell biological and functional characterization of this protein (Saskia van Mil; financed by MLDS grant 98-12). In addition, he continues his work on the molecular diagnostics of hereditary cholestasis.
The research group of Dr. Klomp is embedded in the conditionally financed program UU-36. It forms an integral part of one the main research lines of the UMC Utrecht: 'Developmental Biology and Oncology' and of the corresponding KNAW research school. Leo Klomp is a member of the board of the Dutch Society for Hepatology (NVH) and of the scientific board of the Dutch Digestive Disease Foundation (MLDS).
National collaborations on (diseases of) copper metabolism exist with Dr. C. Wijmenga (Dept. human genetics; UMCU), Dr. M. Merckx (TUE), Dr. RHJ. Houwen (Dept. of Pediatrics, UMCU), Prof. J. Smeitink (KUN) and Prof G. Canters (UL). There is an international collaborations on (diseases of) copper metabolism with Prof. JD Gitlin (Washington University, St. Louis, USA). Furthermore, we collaborate with Dr. C. Ducket, Univ. Michigan, USA, on a possible role of MURR1 in apoptosis.
There are other collaborations with Prof. Dr. GP van Berge Henegouwen (UMCU), Prof. Dr. F. Kuipers (Dept. Pediatrics, Groningen), Prof. Dr. RPJ Oude Elferink (AMC, Amsterdam), Dr. R. Thompson and Dr. A. Knisely (UCL, London, UK) and Dr. LN Bull (UCSF, San Francisco, USA) on cholestasis and hepatobiliary secretion of bile acids.