Keynote Lectures
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Keynote lecture Sunday, Sept. 23rd 6.30 pm–7.30 pm; Room: Lecture Hall 1+2
Genetic and environmental factors for the alcoholism risk
Schuckit M (USA)
Great strides have been made in the last decade regarding the importance of both genetic and environmental contributors to the risk for heavy drinking, alcohol problems, and alcohol use disorders. This lecture reviews recent research findings regarding one potentially important endophenotype contributing to these risks, a low level of response (sensitivity) to alcohol. The genetic findings will highlight several genes that appear to contribute to the level of response to alcohol in both animals and humans (including the l allele of the serotonin transporter and a polymorphism of a potassium channel gene), review ongoing steps to identify additional genes in several large population studies, present the approach being used to extend data to additional relatives for relatively rare polymorphisms contributing to the sensitivity to alcohol, while also presenting information on the search for environmental factors that contribute to the risk. The latter includes the results of structural equation models and growth curve analyses in evaluating models of how an endophenotype (e.g., the low response to alcohol) appears to relate to additional characteristics of the person and the environment in contributing to the heavy drinking and alcohol-related life problems using data from a 25-year prospective study across two generations of San Diego families.
Keynote lecture Monday, Sept. 24th 11.00–12.00 am; Room: Lecture Hall 1+2
Why mice, rats and some humans drink
Tabakoff B, Bhave S, Printz M, Huebner N, Mangion J, Hu W, Saba L, Hornbaker Ch, Hoffman P (USA)
The revolution in high throughput assessment of genetic, genomic and proteomic data has produced novel opportunities to search for genetic contributors to complex phenotypes. Alcohol consumption by animals, including humans, is a quantitative trait which has both genetic and environmental determinants. Much work has been expended to identify the regions of the genome and the actual genes that contribute to the large variation evident within and across species in alcohol consumption. During the past several years, we have developed experimental approaches, generated transcriptome and genetic data, and analyzed data using a process which we call MAGIC-B, to identify genes which differ in their levels of transcription and are involved in modulating alcohol consumption. Whole brain transcriptome information was generated for 30 strains of the BXD RI mouse panel, for 27 strains of the HXB RI rats and for 20 strains of inbred mice. Genetic marker information was generated or obtained from public sources for all strains of animals. Behavioral data on the phenotype of voluntary alcohol consumption, using a two-bottle choice procedure, was generated for all strains of mice and rats. Using this large collection of data, we determined quantitative trait loci for the behavioral phenotype (b-QTLs) and the QTLs for gene expression in brains of mice and rats (e-QTLs). We performed correlation analysis between brain gene expression and voluntary alcohol consumption across the mouse and rat panels of animals. We used the premises of MAGIC-B to filter the correlated genes through the b-QTL and e-QTL filters and arrive at lists of genes whose expression levels correlated with alcohol consumption and whose transcriptional regulatory control was located in the same area of the genome as the b-QTL for alcohol consumption in mice and rats. We then ascertained the location of the ‘candidate’ genes in the human genome and ascertained whether the ‘candidate’ genes were located in QTLs which were determined for alcohol consumption in humans. Overall, this analysis produced the indication for the involvement of the following genes in the quantitative trait of alcohol consumption: Paqr, Map3k, Prpf, Myoc, Galnt1, Nck2, Pcdhga3 and P2rx4. The biochemical pathways and physiologic and behavioral functions determined by these genes will be discussed. Support by NIAAA and the Banbury Fund.
Keynote lecture Tuesday, Sept. 25th 11.00–12.00 am; Room: Lecture Hall 1+2
Amino acids balance as determinant of alcohol dependence
De Witte P (Belgium)
It is now well agreed that an imbalance between neuro-inhibitory and neuro-excitatory amino acids can be held responsible, at least for a large part, for the ethanol withdrawal symptoms leading to craving as well as relapse. The brain's most prevalent inhibitory transmitter substance is gamma-aminobutyric acid (GABA) and the most important excitatory transmitter is L-glutamate (GLU). While there is no clear evidence that ethanol alters extracellular GABA concentrations, studies show that ethanol increases the release of brain taurine, another inhibitory amino acid. Although taurine release seems to be part of an osmoregulatory process, the effects of the released taurine might be greater than the sole regulation of cell volume. Indeed, taurine has been shown to exert a neuromodulatory action by inhibiting neuronal cell excitability. Excitatory amino acids, particularly glutamate, have been implicated in ethanol withdrawal and may be responsible for the seizures, anxiety, hyperexctability and even neuronal death due to excitotoxicity. During withdrawal a dramatic increase in glutamate release was observed in the brain, particularly in the hippocampus. This large glutamate increase could lead to excitotoxicity. Furthermore, arginine, another amino acid, was reduced in chronically alcoholized rats interrupted by repeated withdrawal. Arginine is principally used in the brain for the synthesis of nitric oxide (NO) by nitric oxide synthase (NOS). Ethanol is known to alter NOS synthesis and an excessive utilization of arginine after chronic ethanol intoxication possibly reflect an increase in NO synthesis which activates in turn the release of glutamate via cyclic GMP and then leading to neurotoxicity. The changes in brain arginine content may thus indicate an excessive production of NO, contributing to the milieu of damaging free radical species. These combined alterations in a number of amino acids clearly warrant to study the consequences of amino acids imbalance which involves free radical species as well as other inflammatory pathways.
Keynote lecture Wednesday, Sept. 26th 11.00–12.00 am; Room: Lecture Hall 1+2
Alcohol, liver fibrosis and cirrhosis: From pathogenesis to antifibrotic therapy
Schuppan D (USA)
Cirrhosis is a major determinant of morbidity and mortality in patients with alcohol abuse. Even low grade alcoholic hepatitis frequently progresses to cirrhosis. Progression depends to a large extent on additional environmental factors (second hits) and genetic predisposition. After elimination of alcohol and second hits, such as obesity and hepatitis C, advanced fibrosis and even cirrhosis are (partly) reversible. Novel drugs are aimed at speeding up or inducing reversal of advanced fibrosis/cirrhosis. Numerous agents show antifibrotic efficacy in rodent models of liver fibrosis. However, their validation in patients is difficult due to the slow progression from normal to cirrhosis (10–40 years) and the unreliability of liver biopsy to quantify fibrosis (biopsy sampling error: 30 and 60% for 1 out of 4 fibrosis stages). Current serum fibrosis markers are ill validated and too insensitive to confirm antifibrotic drug effects. Transient elastography adds a new dimension of fibrosis assessment, but is again too insensitive to monitor fibrosis progression or regression. Therefore, much effort is currently invested to develop quantitative imaging of liver fibrosis and fibrogenesis by use of molecular probes that are targeted at collagen or at the fibrogenic cells, and to identify sensitive serum markers of progression and regression by use of advanced transcriptomics and proteomics. Apart from liver transplantation which is only available to a minority of patients with end stage alcoholic liver disease, future reversal therapies are anticipated that use combinations of antifibrotic agents, likely in concert with hepatocyte regenerative approaches, such as stem or progenitor cell transplantation.