The availability of mammalian whole genome sequences, has opened up unprecedented new opportunities for biomedical research. In the pre-genomic era the molecular basis of pathology was evaluated based on hypotheses that specific molecular pathways were involved. Unfortunately this """"""""hypothesis biased"""""""" approach limited discoveries to already known, or easily predicted, molecular explanations. In the post-genomic era we can overcome this limitation and conduct unbiased comprehensive molecular characterizations of pathological events in tissues. Expression arrays can be used to follow changes in transcription levels (mRNA) of all genes expressed in a given tissue (the transcriptome). New proteome technology can be used to detect changes in levels of proteins or in their posttranslational modification. These technologies have lead to an unprecedented explosion in biomedical discoveries and opened many new avenues of research. ? ? The NOD mouse is a model for type I insulin dependent diabetes mellitus. As in the human disease the insulin producing beta cells in the islets of Langerhans are destroyed by an autoimmune process. The induction and earliest pathophysiologic events of this process remains unclear. We will use molecular phenotyping to obtain a comprehensive characterization of developmental events in NOD mice at age 2-4 weeks. This phenotyping will focus on two tissues: 1). The islets, which are the targets of autoimmune destruction, and, 2). The peripheral leukocytes, which are the effectors of that destruction. The objective of this project is to generate data that will help understand the very early pathophysiology in NOD mice, at the molecular level. For this purpose we will pursue the following specific aims:
Aim 1. To characterize the changes in the molecular phenotype that occurs in islets of NOD mice between 2 and 4 weeks of age.
Aim 2. To characterize the changes in the molecular phenotype that occurs in islets of NON, NOD scid and C57Bl6 mice between 2 and 4 weeks of age.
Aim 3. To characterize the changes in the molecular phenotype of spleen leukocytes in NOD mice between 2 and 4 weeks of age.
Aim 4. To characterize the changes in the molecular phenotype of spleen leukocytes that occurs in NON and C57Bl6 mice between 2 and 4 weeks of age. We are convinced that an extensive characterization of the early developments in molecular phenotype of islets and leukocytes in NOD mice will yield new insights into the pathogenic processes and open new avenues of research that could not be opened by traditional investigative approaches.
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