The overall goal of this Program Project is to develop improved vectors for gene delivery in vivo and the application of these vectors for treatment of cardiovascular disease in experimental animals. There are four research projects supported by four core units and complemented by two pilot and feasibility projects. The objective of Project l is to develop and test gutless adenoviral vectors using reporter genes, and to test of the utility of these vectors in the in vivo delivery of the low density lipoprotein receptor (LDLR) and the very low density lipoprotein receptor (VLDLR) genes in the treatment of hypercholesterolemia in experimental animals. In close collaboration with Project 2, helper- dependent adenoviral vectors will be produced and strategies will be developed to ensure long-term expression by transient immunosuppression, use of vectors of different serotypes, and use of gutless adenoviral vectors totally devoid of viral genes. Experimental animals will be normal mice, LDLR -/- mice and heterozygous LDLR-deficient rhesus monkeys. Project 2 will collaborate with Projects 1, 3, and 4 to develop gutless vectors for experiments in vitro and in vivo using helper-dependent viruses that contain viron protein genes from different serotypes. It will also develop integrating adenoviral vectors using a eukaryotic transposable element. Project 3 will apply a drug dependent regulatable system to produce transgenic mice that express LDLR that can be turned on by an exogenous ligand. It will optimize the system for possible use in humans in the future and to incorporate into helper-dependent gutless adenoviral vectors developed in Projects 1 and 2. Project 4 will test systematically the utility of adenoviral gene transfer to diminish the extent of apoptosis after coronary artery ligation, for five complementary classes of protein with proven ability to inhibit apoptosis in vitro. These projects will be supported by an Administrative Core, a Primate Core (at the Southwest Foundation for Biomedical Research where the rhesus monkeys are housed) which conducts the primate experiments ii collaboration with Projects 1, 2 and 3, and Vector Production Core, which produces large amounts of high quality gutless vectors for in vivo use. Two pilot and feasibility projects have been selected from eleven submissions for inclusion in this application. They deal with (i) control of antigen presentation in gene therapy and (ii) apoptosis-based gene therapy of vascular smooth muscle.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-CSR-B (S1))
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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Wang, Leiming; Xu, Mafei; Qin, Jun et al. (2016) MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer. Oncotarget 7:14673-83
Oka, K; Mullins, C E; Kushwaha, R S et al. (2015) Gene therapy for rhesus monkeys heterozygous for LDL receptor deficiency by balloon catheter hepatic delivery of helper-dependent adenoviral vector. Gene Ther 22:87-95
Stephen, Sam Laurel; Montini, Eugenio; Sivanandam, Vijayshankar Ganesh et al. (2010) Chromosomal integration of adenoviral vector DNA in vivo. J Virol 84:9987-94
Li, Luoping; Xie, Xin; Qin, Jun et al. (2009) The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab 9:77-87
Brunetti-Pierri, Nicola; Stapleton, Gary E; Law, Mark et al. (2009) Efficient, long-term hepatic gene transfer using clinically relevant HDAd doses by balloon occlusion catheter delivery in nonhuman primates. Mol Ther 17:327-33
Koeberl, Dwight D; Sun, B; Bird, A et al. (2007) Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia. Mol Ther 15:1253-8
Koeberl, D D; Sun, B D; Damodaran, T V et al. (2006) Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia. Gene Ther 13:1281-9
Oka, Kazuhiro; Chan, Lawrence (2004) Liver-directed gene therapy for dyslipidemia and diabetes. Curr Atheroscler Rep 6:203-9
Zhao, B; Chua, S S; Burcin, M M et al. (2001) Phenotypic consequences of lung-specific inducible expression of FGF-3. Proc Natl Acad Sci U S A 98:5898-903