ponse in situ, vascular damage and hypoxia. Permeability of the BBB leads to seizures, paralysis, unrousable coma and death. The cell and molecular pathways involved in CM pathogenesis are poorly characterized and need to be better understood to identify novel therapeutic targets for intervention. Clinical epidemiological studies in different geographical areas of malaria-endemicity have indicated that the onset, progression and outcome of CM involve a complex interplay between environmental factors, parasite-expressed order Trametinib virulence factors and host genetic factors influencing replication of the parasite or innate or acquired immunity. Genetic studies in humans have pointed to a heritable component to susceptibility to CM, while case-control association studies have suggested a complex and heterogeneous genetic component in CM, including hemoglobin variants, polymorphisms in cytokine genes or gene promotors, and many others. The complex genetic component of CM susceptibility has also been investigated in the mouse model for experimental CM caused by infection with Plasmodium berghei ANKA. P. berghei infection in mice closely mimics P. falciparum-induced CM in humans, with susceptible mouse strains developing an acute cerebral syndrome within 67 days characterized by ataxia, paraplegia, seizures and coma leading to uniform lethality by day 810 post-infection. Like in humans, studies in mouse mutants bearing inactivating mutations at specific A Jak3 Mutation Protects against Cerebral Malaria genes have shown that host-driven inflammation plays a central role in CM pathogenesis. Indeed, local production of proinflammatory cytokines such as IFN-c, TNF-a and LT-a, upregulation of chemokine ligands and cell adhesion molecules, as well as sequestration of immune cells and parasites in the brain microvasculature have all been shown to play a role in CM. On the other hand, inactivating mutations in genes coding for proinflammatory molecules, and generation of anti-inflammatory cytokines like IL-10 and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22184166 IL-4 have been associated with protection from CM. Genome-wide linkage studies in informative crosses derived from mouse strains showing varying degrees of susceptibility to P. bergheiinduced CM have detected at least six quantitative trait loci designated berghei resistance loci as modulating response to infection including survival from acute infection: Berr1, Berr2, Berr3, Berr4, Berr5, and the Cmsc locus mapping to the H-2 region of chromosome 17. The Berr5 locus colocalizes with three other immune loci, including Trl-4, Tsiq2, and Eae19 suggesting the possibility of a common genetic effect underlying these phenotypes. Nevertheless, the modest effects of these individual loci, the relatively large size of the chromosomal regions mapping underneath the QTL peaks, and the large number of positional candidates have precluded the positional cloning of the genes involved. ENU mutagenesis is a powerful experimental tool used to introduce random mutations 
in the mouse germ-line. Such mutations can be propagated in informative pedigrees, where they can be bred to homozygosity, and where their effect on a given physiological system or host pathway can be investigated. In high throughput screening experiments, such mutations may manifest themselves as rare pheno-deviant pedigrees displaying unique disease-associated phenotypes. The positional cloning of the mutant gene, facilitated by the de novo nature of the mutation, may in turn identify novel proteins th
