Novartis Foundation Symposium最新文献

Molecular chaperones are not only fascinating molecular machines that help the folding, refolding, activation or assembly of other proteins, but also have a number of functions. These functions can be understood only by considering the emergent properties of cellular networks--and that of chaperones as special network constituents. As a notable example for the network-related roles of chaperones they may act as genetic buffers stabilizing the phenotype of various cells and organisms, and may serve as potential regulators of evolvability. Why are chaperones special in the context of cellular networks? Chaperones: (1) have weak links, i.e. low affinity, transient interactions with most of their partners; (2) connect hubs, i.e. act as 'masterminds' of the cell being close to several centre proteins with a lot of neighbours; and (3) are in the overlaps of network modules, which confers upon them a special regulatory role. Importantly, chaperones may uncouple or even quarantine modules of protein-protein interaction networks, signalling networks, genetic regulatory networks and membrane organelle networks during stress, which gives an additional chaperone-mediated protection for the cell at the network-level. Moreover, chaperones are essential to rebuild inter-modular contacts after stress by their low affinity, 'quasi-random' sampling of the potential interaction partners in different cellular modules. This opens the way to the chaperone-regulated modular evolution of cellular networks, and helps us to design novel therapeutic and anti-ageing strategies.

Multicellular organisms exist in dynamic equilibrium with bacterial populations, either in the form of the microbiota of the organism or as pathogens. A challenge to 21st century systems biology is to determine the networks of interactions that exist between the prokaryotic and eukaryotic components of multicellular organisms. Bacterial colonization is stressful for both the prokaryotic and eukaryotic components of an organism and it is emerging that the cell stress proteins (CSPs) of both bacteria and host play roles in the interaction between both Kingdoms. In addition to acting intracellularly to fold proteins, it is being established that CSPs have a wide range of moonlighting functions that are relevant to controlling bacterial colonization. Thus host CSPs can act as cell surface receptors to bind bacteria or to respond to their components. Host CSPs are also secreted into the extracellular fluid where they modulate leukocyte function, potentially to activate antibacterial defences. Bacteria, in turn, have evolved CSPs with adhesive properties for the host. Bacterial CSPs can also modulate host leukocyte function and can induce cellular apoptosis. In insects, endosymbiotic bacteria provide bacterial CSPs which are utilised by the host. Bacterial CSPs have also been shown to be antibacterial targets. These findings establish a range of roles for CSPs in bacteria-host interactions.

Eukaryotic and prokaryotic chaperonin 60s (Cpn60s) activate macrophages to produce pro-inflammatory cytokines. CD14 and TLR4 have been proposed as potential Cpn receptors. In addition, Cpn60s can block LPS-induced activation. This is a dose-related effect, low concentrations block, and high concentrations activate. This may relate to the ability of Cpn60s to block inflammatory disease. Cpns are multiplex or moon-lighting proteins, with functions as molecular chaperones, in stress survival and as inflammatory modulators. A cpn60.1 knockout mutant does not induce a granulomatous response and cytokine levels, such as tumour necrosis factor are reduced in the tissues. These data suggest that Cpn60.1 may also function as a virulence factor.

Recent clinical trials have shown that the loss of insulin production that characterizes progressive type 1 diabetes mellitus can be attenuated by treatment with non-FcR binding anti-CD3 monoclonal antibody (mAb). This approach is a first step towards the ultimate goals of treatment: to improve and maintain insulin production. However, additional interventions will be needed because, with time, there is progressive loss of insulin production after treatment with a single course of anti-CD3 mAb. The basis for the long-term loss of insulin production after immune therapy is not known because animal models have not been informative about the mechanisms, and there are not biomarkers of autoimmunity that can be used to monitor the process. Therefore, strategies for clinical testing might involve both beta cell and immunological therapies. Examples of the former include agents such as GLP1 receptor agonists or DPPIV inhibitors which increase beta cell insulin content. Preclinical data suggest that co-administration of antigen with anti-CD3 mAb can induce a tolerogenic response to the antigen that may then be administered to maintain tolerance. In addition, other immunological approaches as well as interventions earlier in the disease process may be successful in maintaining greater beta cell function for extended periods.

A wealth of data in animal models indicates that type 1A diabetes results from T cell-mediated specific destruction of islet beta cells. There is evidence for the NOD mouse model that insulin is the primary autoantigen and a specific insulin peptide B:9-23 is central to pathogenesis. It is also now possible to predict the development of type 1A (immune mediated) diabetes for the great majority of individuals with a combination of genetic, immunological and metabolic parameters. Such prediction is possible because of the chronic nature of the autoimmunity and loss of beta cell function that precedes the disease. Given the ability to predict type 1A diabetes trials at all stages of the disorder to prevent beta cell destruction are now possible.

Neuregulin 1 (Nrg1) and ErbB receptor tyrosine kinase signalling is essential for the formation and proper functioning of multiple organ systems and inappropriate Nrgl/ErbB signalling severely compromises health, contributing to such diverse pathologies as cancer and neuropsychiatric disorders. Numerous genetic modelling studies in mice demonstrate that Nrg1 signalling is important in the development of normal neuronal connectivity. Recent studies have identified novel signalling mechanisms and revealed unexpected roles of Nrg1 isoforms in both the developing and adult nervous system. Of particular interest to this discussion are findings linking deficits in Nrg1-ErbB4 signalling to perturbations of synaptic transmission, myelination, and the survival of particular sets of neurons and glia.

Mucosal administration of autoantigen (insulin) to animal models has been demonstrated to be effective in preventing autoimmune diabetes. Efficacy is dependent upon the dose and the age at which it is delivered. Because of its low toxicity, mucosal administration of insulin represents an attractive preventive therapy in human. Translation of what is efficacious in animal models is, however, challenging. We have proposed mucosal insulin vaccination as a primary prevention strategy in children on the basis that children with extreme type 1 diabetes risk (> 50%) can be identified and that insulin has been shown to be the first target of autoimmunity in children. Novel, and similar to what is efficacious in mice, is that insulin will be administered when the children are still autoantibody negative in order to induce protective immunity prior to initiation of autoimmunity. The efficacy of increasing doses of mucosal insulin to induce protective immunity will be assessed as the primary end point of the trial. The rationale for primary vaccination and the trial strategy are discussed.

Various chronic antidepressant treatments increase adult hippocampal neurogenesis, but the functional importance of this phenomenon remains unclear. Using radiological and genetic methods, we show that disrupting neurogenesis blocks behavioural responses to antidepressants. X-irradiation of a restricted region of mouse brain containing the hippocampus prevented the neurogenic and behavioural effects of two classes of antidepressants. Similarly, a genetic strategy that ablates adult progenitor cells resulted in a lack of effect of antidepressants. In addition, we have identified a form of long-term potentiation in the dentate gyrus that is dependent on the presence of young neurons and which is stimulated by antidepressants. These findings suggest that the behavioural effects of chronic antidepressants require hippocampal neurogenesis and are mediated by an increased synaptic plasticity in the dentate gyrus.

BDNF is a key regulator of synaptic plasticity and hence is thought to be uniquely important for various cognitive functions. While correlations of schizophrenia with polymorphisms in the BDNF gene and changes in BDNF mRNA levels have been reported, specific links remain to be established. Cell biology studies may provide clues as to how BDNF signalling impacts schizophrenia aetiology and pathogenesis: (1) the Val-Met polymorphism in the pro-domain affects activity-dependent BDNF secretion and short-term, hippocampus-mediated episodic memory. (2) pro-BDNF and mBDNF, by interacting with their respective p75(NTR) and TrkB receptors, facilitate long-term depression (LTD) and long-term potentiation (LTP), two common forms of synaptic plasticity working in opposing directions. (3) BDNF transcription is controlled by four promoters, which drive expression of four BDNF-encoding transcripts in different brain regions, cell types and subcellular compartments (dendrites, cell body, etc.), and each is regulated by different genetic and environmental factors. A role for BDNF in early- and late-phase LTP and short- and long-term, hippocampal-dependent memory has been firmly established. Extending these studies to synaptic plasticity in other areas of the brain may help us to better understand how altered BDNF signalling could contribute to intermediate phenotypes associated with schizophrenia.