LAWRENCE C CHAN

..ApoB mRNA editing is the prototype of RNA editing in mammals. What we learn from apoB mRNA editing will be useful in our understanding of other examples of RNA editing in vertebrates which are being described with increasing frequency...

..In the absence of ADFP, impairment of LD formation is associated with the accumulation of microsomal TG but a reduction in TG in other subcellular compartments...

..Terashima, T., Kojima, H., Chan, L. Bone marrow expression of poly(ADP-ribose) polymerase underlies diabetic neuropathy via hematopoietic-neuronal cell fusion...

..Much work remains to be done, however, before this regimen can be taken from the bench to the bedside...

..Tip47 and ADFP in peripheral tissues may play a critical role in regulating the formation and turnover, and hence metabolic consequences, of ectopic fat...

..In conclusion, Adfp inactivation in ApoE(-/-) background protects against atherosclerosis and appears to be a relatively pure model of impaired foam cell formation...

..These experiments uncover the metabolic adaptations associated with the constitutional lipolysis in plin(-/-) mice that allowed the mice to continue to exhibit normal glucose tolerance in the presence of peripheral insulin resistance...

..Here, we investigated the effect of inactivation of beta2 integrins at different stages of atherosclerosis by timed bone marrow transplantation (BMT) of CD18(-/-) cells in low-density lipoprotein receptor knockout (LDLR(-/-)) mice...

..In conclusion, liver-directed gene transfer of human APOA-I using a HD-Ad vector resulted in a reduction of the development of atherosclerosis with the absence of significant toxicity...

..The evidence presented suggests that some of the approaches taken in animals may be ready for clinical trials in the near future...

..These observations are important in considering the development of longer acting GLP-1R agonists for the treatment of type 2 diabetes...

..Recent results on the long-term effect of gene therapy suggest that hepatic expression of therapeutic genes suppresses inflammation and has profound effects on the nature of the atherogenic process...

..p21 is also involved in the maturation and differentiation of monocytes into macrophages...

..We used helper-dependent adenovirus (HD-Ad) gene transfer to examine the effect of long-term hepatic apoA-I expression on atherosclerotic lesion progression and remodeling in a mouse model of familial hypercholesterolemia...

..Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes...

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..The development of DRG neuron-targeted HDAd with proven efficacy in a preclinical model may have implications for the treatment of sensory neuronopathies of diverse etiologies...

..The alteration of LD size in the liver of Lep(ob/ob)/Adfp(-/-) mice despite the relocation of other LDPs to the LD indicates a nonredundant role for ADFP in determining the size and distribution of hepatic LDs...

..In addition, SRC-2 ablation, in both a whole-body and liver-specific manner, resulted in a Von Gierke's disease phenotype in mice. Our results position SRC-2 as a critical regulator of mammalian glucose production...

..This paradigm of induced transdetermination of receptive progenitor cells in vivo may be generally applicable to therapeutic organogenesis for multiple diseases, including diabetes...

..T cells also play important roles in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity...

..Thus, although EL modulated lipoprotein profile in mice, there was no effect of EL inactivation on atherosclerosis development in two hyperlipidemic atherosclerosis-prone mouse models...

..These studies demonstrate that it is possible to restore type VII collagen gene expression in RDEB skin in vivo...

..In this study, we investigated how macrophage-specific loss of p53 function might modulate atherosclerosis development in LDL receptor-deficient mice, a model for familial hypercholesterolemia...

..CONCLUSION: Loss of Pnpla3 does not cause fatty liver, liver enzyme elevation, or insulin resistance in mice...

..The biochemical pathways involved in obesity resistance in plin(-/-) mice identified in this study may represent potential targets for the treatment of obesity...

..Plasma C-reactive protein (CRP) concentration is a strong predictor of atherosclerosis. However, to date, there is no in vivo evidence that CRP is proatherogenic...

..A novel strategy for gene therapy for diabetes was published recently. Gene therapy for dyslipidemia and diabetes is still in its infancy. Nonetheless, recent progress in this area is encouraging and bodes well for the future...

..Scavenger receptor-class B type I (SR-BI) is an HDL receptor that mediates the selective uptake of cholesteryl ester. This study investigates the role of EL and SR-BI in the regulation of HDL metabolism in gene knockout mouse models...

..These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes...

..Thus, COUP-TFII regulates adipogenesis by regulating the key molecules in adipocyte development and can serve as a target for regulating energy metabolism...

..These results suggest that a VLDLR variant lacking the third complement-type repeat is generated by neuron-specific alternative splicing. Such differential splicing may result in different lipid uptake in neurons and astrocytes...

..Taken together, these findings suggest that a failure of local endogenous resolution mechanisms may underlie the unremitting inflammation that fuels atherosclerosis...

..We conclude that CAR activation improves type 2 diabetes, and that these actions of CAR suggest therapeutic approaches to the disease...

..We found that all three forms of chronic extravascular inflammation had no effect on the rate of atherosclerosis development...

..Loss of Bscl2 function thus interferes with the normal transcriptional cascade of adipogenesis during fat cell differentiation, resulting in near total loss of fat or lipodystrophy...

..Overall, we provide evidence that loss of adiponectin induces a primary state of endothelial dysfunction with increased leukocyte-endothelium adhesiveness...

..CONCLUSIONS: Chronic nicotine exposure augments atherosclerosis by enhancing the production of proinflammatory cytokines by macrophages, which, in turn, activate atherogenic NF-kappaB target genes in the aortic lesions...

..Given these capabilities, this vector represents a paradigm for the gene therapy of HTN...

..Vector characterization and troubleshooting are also provided at appropriate steps...

..Taken together, our results identify a link between lipid and glucose metabolism mediated by the FXR-SHP cascade...

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..These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance...

..Space limitation has precluded a complete cataloging of all publications on the topic. We instead highlight some of the salient developments in the last few years...

..We will examine the pros and cons of each strategy as well as the hurdles that must be overcome before these approaches to generate new beta-cells will be ready for clinical application...

..These observations have implications for the regulation of insulin gene expression, modulation of self-tolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes...

..The orphan nuclear receptor ERRgamma is expressed in BAT and its transactivation of the PGC-1alpha promoter is potently inhibited by SHP. We conclude that SHP functions as a negative regulator of energy production in BAT...

..Because prohibitin is also expressed in blood vessels of human white fat, this work may lead to the development of targeted drugs for treatment of obese patients...

..We conclude that EL is a major determinant of HDL concentration, structure, and metabolism in mice, and a major determinant of HDL concentration in humans...

..In conclusion, our study indicates that absence of adipo causes increased beta-oxidation but does not cause glucose intolerance or insulin resistance in mice...

..We discussed the pros and cons of the different strategies that are being used to re-invent the pancreatic b cell...

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..Further research is necessary, however, to better define the most effective pro-endocrine factors and the most amenable cell types to achieve transdifferentiation for beta cell replacement...

..In conclusion, we found that pancreatic beta cells express AQP7, which appears to be a key regulator of intraislet glycerol content as well as insulin production and secretion...

..Included are protocols for Southern blot analysis to monitor vector amplification, slot blot assay to determine the infectious titer of the purified HDAd, and real-time PCR to detect helper virus contamination in the preparation...

..Included are protocols for Southern blot analysis to monitor vector amplification, slot blot assay to determine the infectious titer of the purified HDAd, and real-time PCR to detect helper virus contamination in the preparation...

..Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation...

..Hence, chronically, ghrelin controls glucose homeostasis by regulating pancreatic Ucp2 expression and insulin sensitivity...

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..This study uncovers a role of Glis3 for regulation of insulin gene expression and expands our understanding of its role in the beta cell...

..We conclude that individual subdomains in the GSM (MCR I through V) play diverse but crucial roles in cooperation with essential trans-acting cofactors such as 14-3-3 proteins to mediate the glucose response of ChREBP...

..This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation...

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..We will study the molecular and cellular mechanisms involved in these processes and events. ..

..We believe that the mechanistic experiments proposed will advance our understanding of lipid and carbohydrate metabolism, energy homeostasis, and atherosclerosis. ..

..Thus, the overall project is highly relevant to lipid nutrient absorption and homeostasis. Significantly, it also provides important information on a newly described pathway in posttranscriptional gene regulation. ..

..In summary, this application utilizes state-of-the-art gene delivery technology plus a conditional knockout model to examine important issues in MTP biology, tissue-specific gene targeting, and intestinal gene therapy. ..

..We are hopeful that the Program will play a significant role in reversing the national trend of increasing numbers of well-trained physicians leaving an academic research oriented career in biomedicine. ..

..We will study the molecular and cellular mechanisms involved in these processes and events. ..

..Specific Aims 2 and 3 will further explore this novel therapy by mechanistic experiments in mice and testing the therapy in nonhuman primates in collaboration with SFBR. ..

..Finally, the best regimens identified by the experiments proposed are strong candidates for clinical trials in the future. ..

..If the treatment strategy ameliorates diabetes in baboons without significant toxic side effects, then it will be an important proof-of-principle experiment that will pave the way for possible clinical trials in the future. ..

..Specific Aims 2 and 3 will further explore this novel therapy by mechanistic experiments in mice and testing the therapy in nonhuman primates in collaboration with SFBR. ..

..The overall project represents an in-depth study on the role of an enzyme, 15-LO, and a particular cell type, macrophages, in atherosclerosis initiation and progression in animal models in vivo. ..

..The project may provide important information related to lipoprotein metabolism and atherosclerosis and a novel pathway involved in the posttranscriptional regulation of gene expression. ..