The G protein-coupled P2Y 2 nucleotide receptor (P2Y 2 R) is upregulated in response to stress and tissue injury and has been postulated to play a role in chronic inflammation seen in atherosclerosis, Alzheimer's disease and Sjögren's syndrome. The role of P2Y 2 R upregulation in vivo is poorly understood, in part due to the lack of a P2Y 2 R overexpressing animal model. The P2Y 2 R overexpressing transgenic rat was generated using a lentiviral vector. Rats overexpressing P2Y 2 R showed a significant increase in P2Y 2 R mRNA levels in all tissues screened as compared to nontransgenic rats. Fura 2 imaging of smooth muscle cells (SMCs) isolated from aorta indicated that the percentage of cells exhibiting increases in the intracellular free calcium concentration in response to P2Y 2 R agonists was significantly greater in freshly isolated SMCs from transgenic rats than wild-type controls. Histopathological examination of tissues revealed that P2Y 2 R overexpressing rats develop lymphocytic infiltration in lacrimal glands and kidneys as early as at 3 months of age. These rats show similarities to patients with Sjögren's syndrome who display lymphocyte-mediated tissue damage. This transgenic rat model of P2Y 2 R overexpression may prove useful for linking P2Y 2 R upregulation with chronic inflammatory diseases, neurodegenerative diseases and Sjögren's syndrome.
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) tract that leads to motor, cognitive and psychiatric impairment. Currently there is no cure for HD. A transgenic HD nonhuman primate (HD-NHP) model was developed with progressive development of clinical and pathological features similar to human HD, which suggested the potential preclinical application of the HD-NHP model. Elevated expression of miR-196a was observed in both HD-NHP and human HD brains. Cytotoxicity and apoptosis were ameliorated by the overexpression of miR-196a in HD-NHP neural progenitor cells (HD-NPCs) and differentiated neural cells (HD-NCs). The expression of apoptosis related gene was also down regulated. Mitochondrial morphology and activity were improved as indicated by mitotracker staining and the upregulation of CBP and PGC-1α in HD-NPCs overexpressing miR-196a. Here we demonstrated the amelioration of HD cellular phenotypes in HD-NPCs and HD-NCs overexpressing miR-196a. Our results also suggested the regulatory role of miR-196a in HD pathogenesis that may hold the key for understanding molecular regulation in HD and developing novel therapeutics.