The molecular mechanism of cholestatic itch

Projectomschrijving

Cholestatische jeuk

Jeuk is een belangrijk symptoom bij patiënten met chronische cholestase (galstuwing). Deze jeuk kan optreden bij elke vorm van cholestase, maar de meest voorkomende vorm is zwangerschapscholestase. Ongeveer 1% van de zwangere vrouwen ontwikkelt jeuk in het derde trimester van de zwangerschap en deze jeuk verdwijnt weer na de bevalling. Bij patiënten met een chronische leverziekte kan de voortdurende jeuk zeer belastend zijn en zelfs de primaire indicatie voor levertransplantatie worden.

Enzym autotaxine

Er is nog weinig bekend over het moleculair mechanisme van cholestatische jeuk. Wij hebben gevonden dat de mate van jeuk sterk correleert met de activiteit van het enzym autotaxine in het plasma. Dit enzym vormt een lipide, lysofosfatidaat (LPA), dat een zeer sterke signaalfunctie heeft via een zestal LPA receptoren die ook op sensorische neuronen aanwezig zijn.
Doel van dit project is om te onderzoeken hoe autotaxine een rol speelt in het induceren of versterken van jeuk tijdens cholestase

Producten

Titel: Pathogenesis and treatment of pruritus in cholestasis
Auteur: Kremer, AE; Beuers, U; Oude Elferink, RPJ; Pusl, T.
Magazine: Drugs
Titel: Advances in Pathogenesis and Management of Pruritus in Cholestasis
Auteur: Kremer, Andreas E., Bolier, Ruth, van Dijk, Remco, Oude Elferink, Ronald P.J., Beuers, Ulrich
Magazine: Digestive Diseases
Titel: Lysophosphatidic acid is a potential mediator of cholestatic pruritus
Auteur: kremer,AE; Martens, JJ; Kulik, W; Ruëff, F; Kuiper, EMM; van Buuren, HR; van Erpecum, KJ; Kondrackiene, J; Prieto, J; Rust, C; Geenes, VL; Williamson, C; Moleanaar, WH; Beuers, U; Oude Elferink, RPJ.
Magazine: Gastroenterology
Titel: the role of autotaxin and lysophosphatidic acid in pruritus of cholestasis
Auteur: Oude Elferink, R; Bolier, R; Beuers, U
Magazine: Hepatology
Titel: Pruritus in liver disease
Auteur: Kremer, AE; Mailette de Buy Wenniger, L; Oude Elferink, RP; Beuers,U.
Magazine: Nederlands Tijdschrift voor Geneeskunde
Titel: Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum
Auteur: Abu-Hayyeh, Shadi, Ovadia, Caroline, Lieu, TinaMarie, Jensen, Dane D., Chambers, Jenny, Dixon, Peter H., Lövgren-Sandblom, Anita, Bolier, Ruth, Tolenaars, Dagmar, Kremer, Andreas E., Syngelaki, Argyro, Noori, Muna, Williams, David, Marin, Jose J.G., Monte, Maria J., Nicolaides, Kypros H., Beuers, Ulrich, Oude-Elferink, Ronald, Seed, Paul T., Chappell, Lucy, Marschall, Hanns-Ulrich, Bunnett, Nigel W., Williamson, Catherine
Magazine: Hepatology
Titel: lysophosphatidic acid and signaling in sensory neurons
Auteur: Oude Elferink RP; Bolier AR; Beuers U.
Magazine: BioChim BioPhys ACta
Titel: Enteroendocrine cells are a potential source of serum autotaxin in men
Auteur: Bolier, Ruth, Tolenaars, Dagmar, Kremer, Andreas E., Saris, Job, Parés, Albert, Verheij, Joanne, Bosma, Piter J., Beuers, Ulrich, Oude Elferink, Ronald P.J.
Magazine: BBA Molecular basis of disease
Titel: Serum Autotaxin Activity Correlates With Pruritus in Pediatric Cholestatic Disorders
Auteur: Kremer, Andreas E., Gonzales, Emmanuel, Schaap, Frank G., Oude Elferink, Ronald P.J., Jacquemin, Emmanuel, Beuers, Ulrich
Magazine: Journal of Pediatric Gastroenterology and Nutrition
Titel: Advances in pathogenesis and treatment of pruritus
Auteur: Bolier,R; Oude Elferink, RP; Beuers, U.
Magazine: Clinical Liver Disease
Titel: Pathophysiology and current management of pruritus in liver disease
Auteur: Kremer, AE; Oude Elferink, RP; Beuers, U.
Magazine: Clinical Research in Hepatology and Gastroeneterology
Titel: Total bile acids in the maternal and fetal compartment in relation to placental ABCG2 expression in preeclamptic pregnancies complicated by HELLP syndrome
Auteur: Jebbink, Jiska, Veenboer, Geertruda, Boussata, Souad, Keijser, Remco, Kremer, Andreas E., Elferink, Ronald Oude, van der Post, Joris, Afink, Gijs, Ris-Stalpers, Carrie
Magazine: Pregnancy Hypertension;An International Journal of Women's Cardiovascular health
Titel: Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy
Auteur: Kremer, Andreas E., Bolier, Ruth, Dixon, Peter H., Geenes, Victoria, Chambers, Jenny, Tolenaars, Dagmar, Ris-Stalpers, Carrie, Kaess, Bernhard M., Rust, Christian, van der Post, Joris A., Williamson, Catherine, Beuers, Ulrich, Oude Elferink, Ronald P.J.
Magazine: Journal of Hepatology
Titel: Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study
Auteur: Hegade, Vinod S, Kendrick, Stuart F W, Dobbins, Robert L, Miller, Sam R, Thompson, Douglas, Richards, Duncan, Storey, James, Dukes, George E, Corrigan, Margaret, Oude Elferink, Ronald P J, Beuers, Ulrich, Hirschfield, Gideon M, Jones, David E
Magazine: Lancet
Titel: Receptors, cells and circuits involved in pruritus of systemic disorders
Auteur: Kremer, AE; Feramisco, J; Reeh, PW; Beuers, U; Oude Elferink, RP.
Magazine: BioChim BioPhys ACta
Titel: Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: Conjugated hypercholanemia without a clear clinical phenotype
Auteur: Vaz, Frédéric M., Paulusma, Coen C., Huidekoper, Hidde, de Ru, Minke, Lim, Cynthia, Koster, Janet, Ho-Mok, Kam, Bootsma, Albert H., Groen, Albert K., Schaap, Frank G., Oude Elferink, Ronald P. J., Waterham, Hans R., Wanders, Ronald J.A.
Magazine: Hepatology
Titel: Pruritus in cholestasis: facts and fiction
Auteur: Beuers,U; Kremer, AE; Bolier,R; Oude Elferink,RP.
Magazine: Hepatology
Titel: Steroid binding to Autotaxin links bile salts and lysophosphatidic acid signalling.
Auteur: Keune WJ, Hausmann J, Bolier R, Tolenaars D, Kremer A, Heidebrecht T, Joosten RP, Sunkara M, Morris AJ, Matas-Rico E, Moolenaar WH, Oude Elferink RP, Perrakis A.
Magazine: Nature Communications
Titel: Serum autotaxin is increased in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions
Auteur: Kremer, AE; van Dijk, RV; Leckie, P: Schaap, FG; Kuiper, EM; Mettang,T; Reiners, KS; Raap, U; Buuren HR; van Erpecum, KJ; Davies, NA; Rust, C; Engert,A; Jalan, R; Oude Elferink, RPJ; Beuers, U.
Magazine: Hepatology
Titel: Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: Conjugated hypercholanemia without a clear clinical phenotype
Auteur: Vaz, Frédéric M., Paulusma, Coen C., Huidekoper, Hidde, de Ru, Minke, Lim, Cynthia, Koster, Janet, Ho-Mok, Kam, Bootsma, Albert H., Groen, Albert K., Schaap, Frank G., Oude Elferink, Ronald P. J., Waterham, Hans R., Wanders, Ronald J.A.
Magazine: Hepatology
Titel: Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study
Auteur: Hegade, Vinod S, Kendrick, Stuart F W, Dobbins, Robert L, Miller, Sam R, Thompson, Douglas, Richards, Duncan, Storey, James, Dukes, George E, Corrigan, Margaret, Oude Elferink, Ronald P J, Beuers, Ulrich, Hirschfield, Gideon M, Jones, David E
Magazine: Lancet
Titel: Advances in pathogenesis and treatment of pruritus
Auteur: Bolier, R; Oude Elferink, RP; Beuers, U.
Magazine: Clinical Liver Disease
Titel: Autotaxin activity has a high accuracy to diagnose intrahepatic cholestasis of pregnancy
Auteur: Kremer, Andreas E., Bolier, Ruth, Dixon, Peter H., Geenes, Victoria, Chambers, Jenny, Tolenaars, Dagmar, Ris-Stalpers, Carrie, Kaess, Bernhard M., Rust, Christian, van der Post, Joris A., Williamson, Catherine, Beuers, Ulrich, Oude Elferink, Ronald P.J.
Magazine: Journal of Hepatology
Titel: Lysophosphatidic acid and signaling in sensory neurons
Auteur: Oude Elferink, Ronald P.J., Bolier, Ruth, Beuers, Ulrich H.
Magazine: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Titel: The molecular mechanism of cholstatic pruritus
Auteur: Oude Elferink, RP; Kremer, AE; Martens, JJ; Beuers, UH.
Magazine: Digestive Diseases
Titel: Mediators of pruritus during cholestasis
Auteur: Oude Elferink, RPJ; Kremer AE; Beuers, U.
Magazine: Current Opinion in Gastroenterology
Titel: Advances in pathogenesis and management of of pruritus in cholestasis
Auteur: Kremer, AE; Bolier,R; van Dijk,R; Oude Elferink, RP; Beuers,U.
Magazine: Digestive Diseases
Titel: Serumautotaxin is increased in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions
Auteur: Kremer, AE; van Dijk, R; Leckie,P; Schaap, FG; Kuiper,EM; Mettang,T; Reiners,KS; Raap, U; Buuren, HR; van Erpecum, KJ; Davies,NA; Rust,C; Engert,A; Jalan, R; Oude Elferink,RP; Beuers,U;
Magazine: Hepatology
Titel: Lysophosphatidic acid and signaling in sensory neurons
Auteur: Oude Elferink, Ronald P.J., Bolier, Ruth, Beuers, Ulrich H.
Magazine: Biochimica et Biophysica Acta
Titel: Prognostic and mechanistic potential of progesterone sulfates in intrahepatic cholestasis of pregnancy and pruritus gravidarum
Auteur: Abu-Hayyeh, Shadi, Ovadia, Caroline, Lieu, TinaMarie, Jensen, Dane D., Chambers, Jenny, Dixon, Peter H., Lövgren-Sandblom, Anita, Bolier, Ruth, Tolenaars, Dagmar, Kremer, Andreas E., Syngelaki, Argyro, Noori, Muna, Williams, David, Marin, Jose J.G., Monte, Maria J., Nicolaides, Kypros H., Beuers, Ulrich, Oude-Elferink, Ronald, Seed, Paul T., Chappell, Lucy, Marschall, Hanns-Ulrich, Bunnett, Nigel W., Williamson, Catherine
Magazine: Hepatology
Titel: Total bile acids in the maternal and fetal compartment in relation to placental ABCG2 expression in preeclamptic pregnancies complicated by HELLP syndrome
Auteur: Jebbink, Jiska, Veenboer, Geertruda, Boussata, Souad, Keijser, Remco, Kremer, Andreas E., Elferink, Ronald Oude, van der Post, Joris, Afink, Gijs, Ris-Stalpers, Carrie
Magazine: Biochimica et Biophysica Acta
Titel: Sodium Taurocholate Cotransporting Polypeptide (SLC10A1) Deficiency: Conjugated Hypercholanemia Without a Clear Clinical Phenotype
Auteur: Vaz FM, Paulusma CC, Huidekoper H, de Ru M, Lim C, Koster J, Ho-Mok K, Bootsma AH, Groen AK, Schaap FG, Oude Elferink RPJ, Waterham HR, Wanders RJA
Magazine: Hepatology
Titel: Molecular mechanisms of pruritus in cholestasis
Auteur: Andreas E. Kremer

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Samenvatting van de aanvraag

In many systemic disorders pruritus (itch) represents an important clinical problem that imposes considerable burden to the patient. Pruritus is also a frequent symptom in patients with cholestatic liver diseases. Pruritus may be mild and tolerable, but it can also be excruciating, causing sleep deprivation or even suicidal ideations. In rare cases, intractable pruritus may become a primary indication for liver transplantation. The molecular mechanism of itch signal transduction is largely unclear. However, in the last decade more information has become available on potential mechanisms that lead to itch perception. In this project we plan to elucidate which mechanisms play a role in cholestatic itch perception. During cholestasis compounds accumulate in plasma that are normally excreted into bile. It is our hypothesis that these compounds act as direct or indirect pruritogens by affecting receptor mediated signalling in itch fibers. Along the lines of this hypothesis we have screened plasma samples of a large group of patients with various cholestatic conditions; mainly women with intrahepatic cholestasis of pregnancy (ICP) and primary biliary cirrhosis (PBC) (Kremer et al. Gastroenterology 2010 in press). In our screen we tested the capacity of plasma samples to activate neuroblastoma cells. Quite strikingly, we found that samples from itchy cholestatic patients caused a significantly higher activation than samples from non-itchy cholestatic patients and from healthy controls. Analysis of the responsible agent revealed lysophosphatidic acid (LPA) as the active compound. LPA is a very potent signalling lipid that can activate cells through various LPA receptors. Subsequently, we could demonstrate that plasma levels of the enzyme autotaxin are strongly increased in cholestatic patients with pruritus. Autotaxin is the enzyme that converts lysophosphatidylcholine (LPC) into LPA. In fact, there was a highly significant correlation between the ATX level in plasma and the severity of itch (as indicated by patients on a visual analogue scale). This is a striking finding as autotaxin has never been connected to itch perception thus far. On the other hand it is thought to play a role in tumour metastasis and wound healing but more recently it has also been found to mediate neuropathic pain. We have also shown that LPA, when injected intradermally, causes itch in mice. On the basis of our results we hypothesize that during cholestasis expression of autotaxin is induced and gives rise to increased local formation of LPA near unmyelinated nerve ending of itch fibers. LPA then activates these neurons through one of the LPA receptors, which activates a specific phospholipase C (PLCbeta3) and gives rise to calcium mobilization. This in turn potentiates action potentials along itch fibers. Hence, aim of this program is to elucidate the role of autotaxin in cholestatic pruritus and possibly also in other forms of systemic itch. This includes the following lines of research: 1. The mechanism and source of increased plasma autotaxin levels in cholestatic pruritus. 2. The mechanism of LPA-mediated activation of sensory neurons. 3. Development of an in vivo animal model for cholestatic itch. 4. Analysis of the role of ATX in other disorders associated with pruritus. Research line 1 will be approached by analysis of autotaxin expression in tissues of cholestatic mice. The mechanism of induced ATX expression will be analysed with reporter constructs of the autotaxin promotor region. For line 2 we will analyze activation of human neuroblastoma cells and neurons from dorsal root ganglions. For line 3 we have developed and validated an automated behavioural scratch assay in mice, which highly specifically quantitates scratch movements. For line 4 we are collecting plasma samples from patient populations with various disorders associated with itch. These research lines will unravel the role of ATX in cholestatic pruritus and possibly also other pruritic conditions. Since highly potent inhibitors of ATX have already been developed and are available through collaboration, this research will also allow development of therapy to relieve this agonizing symptom.

Onderwerpen

Kenmerken

Projectnummer:
91210054
Looptijd: 100%
2011
2017
Onderdeel van programma:
Gerelateerde subsidieronde:
TOP subsidies - 2010 ZonMw R3
Projectleider en penvoerder:
Prof. dr. R.P.J. Oude Elferink
Verantwoordelijke organisatie:
Amsterdam UMC - locatie AMC