We are employing DNA viruses as molecular probes to study genome expression in human cells. We are studying intensively the structure and function of a human parvovirus, adeno-associated virus (AAV). AAV has been developed as a eukaryotic expression vector. AAV normally grows in cells only in the presence of a helper virus (either adenovirus or herpesvirus). In the absence of any helper, the AAV genome integrates into the cell chromosome. Thus, the AAV vector is useful as a transducing virus for high frequency integration of genes into mammalian cell chromosomes to yield stable expression. This vector also may be useful for gene therapy. We are now analyzing intensely the control of gene regulation in AAV vectors in order to maximize the expression of foreign genes introduced into mammalian cells using this vector. We have discovered a complex system of gene regulation mediated by products of the AAV rep gene which are required for replication of AAV DNA but also mediate transcriptional activation and translational inhibition of some genes. Site-specific mutagenesis is being used to resolve these functions. Coding of all these functions in a single gene is unique in eukaryotic systems. Adenovirus is the helper for AAV. This relationship is being analyzed. Both AAV and adenovirus recombine with cellular DNA. In the case of adenovirus this causes malignant transformation of the cell. EAVE inhibits this transformation and also,inhibits Adl2 oncogenesis in newborn animals. Thus, EAVE inhibits tumor induction. The mechanism of this inhibition of tumor induction is being studied at the molecular level in cell culture. We also are analyzing interactions of EAVE with HIV as a potential approach to a novel therapy for AIDS. We are also developing EAVE vectors that express the CFTR gene as a potential gene therapy for cystic fibrosis.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Xu, Xin; Zheng, Liwei; Yuan, Quan et al. (2018) Transforming growth factor-? in stem cells and tissue homeostasis. Bone Res 6:2
Bian, Qin; Jain, Amit; Xu, Xin et al. (2016) Excessive Activation of TGF? by Spinal Instability Causes Vertebral Endplate Sclerosis. Sci Rep 6:27093
Xie, Liang; Tintani, Francis; Wang, Xiao et al. (2016) Systemic neutralization of TGF-? attenuates osteoarthritis. Ann N Y Acad Sci 1376:53-64
Cui, Zhuang; Crane, Janet; Xie, Hui et al. (2016) Halofuginone attenuates osteoarthritis by inhibition of TGF-? activity and H-type vessel formation in subchondral bone. Ann Rheum Dis 75:1714-21
Qiu, Tao; Xian, Lingling; Crane, Janet et al. (2015) PTH receptor signaling in osteoblasts regulates endochondral vascularization in maintenance of postnatal growth plate. J Bone Miner Res 30:309-17
Xu, Xin; Zheng, Liwei; Bian, Qin et al. (2015) Aberrant Activation of TGF-? in Subchondral Bone at the Onset of Rheumatoid Arthritis Joint Destruction. J Bone Miner Res 30:2033-43
Crane, Janet L; Cao, Xu (2014) Bone marrow mesenchymal stem cells and TGF-? signaling in bone remodeling. J Clin Invest 124:466-72
Crane, Janet L; Zhao, Luo; Frye, Joseph S et al. (2013) IGF-1 Signaling is Essential for Differentiation of Mesenchymal Stem Cells for Peak Bone Mass. Bone Res 1:186-94
Zhen, Gehua; Wen, Chunyi; Jia, Xiaofeng et al. (2013) Inhibition of TGF-? signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 19:704-12
Yu, Bing; Zhao, Xiaoli; Yang, Chaozhe et al. (2012) Parathyroid hormone induces differentiation of mesenchymal stromal/stem cells by enhancing bone morphogenetic protein signaling. J Bone Miner Res 27:2001-14

Showing the most recent 10 out of 19 publications