Down Syndrome (aka Trisomy-21), which affects approximately one of every 700 babies born in the United States each year, is characterized by varying degrees of stunted cognitive and physical ability as well as characteristic facial and body features. The extent to which an individual will be able to integrate into society is determined by the severity of the condition as well as the timing and extent of intervention. Historically, intervention has included screening with subsequent dedicated therapy and training. However, recent work on the etiology of Down Syndrome (see Lu et al., below) has suggested that inhibition of a chromosome 21 (HSA21)-associated, oligodendrocyte transcription factor (OLIG2) may blunt the effects of over-expression of a subset of HSA21 genes that inhibit the growth of neural progenitors, which are necessary for normal brain development. This approach provides new hope for a prevalent disease with a tremendous burden on society and for which no medical treatment exists. (more...)

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Progerias are rare genetic diseases characterized by premature aging including: retarded growth, osteoporosis, alopecia, and ultimately occlusive vascular disease. Many progeriod disorders are caused by mutations that lead to the accumulation of a lipid-modified form of prelamin A (farnesyl-prelamin A), resulting in a disruption of the cell nucleus. Zmpste24 is a mammalian integral membrane metalloproteinase that is critical for the processing of farnesylated proteins containing the carboxyl-terminal CAAX motif. Zmpste24, an ortholog of the yeast protein Ste24p, acts as an endoprotease by cleaving the 15 amino acids from the C terminus of prelamin A (including the farnesyl group), releasing mature lamin A. (more...)

To meet the constant energy requirement in the face of highly variable food supply, mammals employ intricate and precise mechanisms for energy storage. When total energy intake is in excess of energy expenditure such as after a meal, excess carbohydrates are converted to fatty acids (de novo lipogenesis). Excess fatty acids are then converted to triacylglycerol to be stored in adipose tissue and released as oxidative fuels for other tissues during times of energy need such as fasting and exercise. The present invention describes for the first time that DNA-dependent protein kinase, DNA-PK, is connected to the signaling pathway involved in the formation of fat from carbohydrate in the liver. The enzymes that are involved in fatty acid and fat synthesis are tightly regulated during fasting/feeding. In the fed condition, especially after a high carbohydrate meal, activities of these enzymes drastically increase as blood glucose and insulin levels rise. The present invention demonstrates that DNA-PK regulates the transcription of fatty acid synthase (FAS), a central lipogenic enzyme that plays a crucial role in de novo lipogenesis by catalyzing all of the seven reactions involved in fatty acid synthesis. Therefore, DNA-PK is a pharmacological target for regulation of obesity and diabetes due to a diet high in carbohydrates. (more...)

The success of gene therapy methods such as small fragment homologous recombination and cDNA-based gene therapies is often difficult to quantify. These methods often lack an endogenous selection mechanism that can be used to differentiate and quantify targeted cells. Therefore, it is difficult to monitor and map the success of gene therapy in patients. UCSF investigators have developed methods and compounds enabling the measurement of expression of mutated and non-mutated alleles in the tissue or cells of a human subject. The method, an in situ RT-PCR assay, can be used for diagnosis of allelic variation and the monitoring of gene therapy for a variety of gene-based diseases, especially cystic fibrosis. (more...)

Platform for Testing the Effects of Human PTP1B Inhibition on Insulin Signaling, Adipose Differentiation and Glucose Uptake (more...)