Research Groups
Molecular Medicine
Research Interests and Description
Group Leader: Mauro Giacca, MD, PhDGroup Members
Research Interests
Gene therapy of cardiovascular disorders, adeno-associated virus (AAV), angiogenesis, Molecular biology of HIV-1 infection.
Description of Research
The Group has two main interests in the field of
Molecular Medicine. One project exploits viral vectors based on the
adeno-associated virus (AAV) to deliver to the heart and the skeletal muscle
different genes that induce therapeutic angiogenesis and tissue regeneration. AAV vectors offer a number
of interesting characteristics that render them appealing for human gene
therapy, among which the high efficiency transduction of post-mitotic cells in
vivo (including cardiomyocytes, skeletal myoblasts, neurons and retinal cells),
the persistence of transgene expression, and the lack of induction of
inflammatory or immune responses. By using this vector class, the laboratory is
currently exploring the effects of several genes involved in angiogenesis
(among which different VEGF isoforms, PlGF, angiopoietin-1, and IGF-1) and
myocardial development (activated Notch-1, Jagged-1) in small and large animal
models of cardiovascular injury. The laboratory is also interested in some
basic aspects of the molecular biology of AAV, with particular reference to the
identification of the cellular proteins that regulate AAV infection. In this
field, the laboratory has recently discovered that members of the MRN (Mre11, Rad50,
Nbs1) complex of the cellular DNA damage repair system play a major role in
regulating cell permissivity to AAV infection.
A second major interest of
the Group is in the field of AIDS research. This project focuses on unraveling the
molecular properties of different HIV-1 proteins, with particular reference to
the processes of viral integration and transcription. The laboratory has
contributed to the understanding of the role that chromatin exerts on viral
gene expression and to its regulation by the viral Tat transactivator. It has
also explored the molecular mechanisms that allow Tat to be released from the
expressing cells and be uptaken by neighboring cells when present in the
extracellular environment, a property that can be largely exploited for
transcellular protein transduction. Another interest of the laboratory is the
viral protein Integrase, which is essential for the integration of the proviral
DNA into the host cell genome. The laboratory has recently discovered that this
enzyme is post-translationally regulated by acetylation and phosphorylation and
that, in particular, the latter modification is essential for HIV-1 genome
integration in resting T-lymphocytes. Finally, the laboratory maintains a
long-standing interest in the elucidation of the molecular mechanisms that
control the initiation of DNA replication in mammalian cells at mammalian
origins of DNA replication.
Recent Publications
Manganaro, L., Lusic, M., Gutierrez, M.I., Cereseto, A., Del Sal, G., Giacca, M. 2010. Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4(+) T lymphocytes. Nat. Med. (Epub ahead of print] Pubmed link
Paolinelli, R., Mendoza-Maldonado, R., Cereseto, A., Giacca, M. 2009. Acetylation by GCN5 regulates CDC6 phosphorylation in the S phase of the cell cycle. Nat Struct Mol Biol. 16, 412-420 Pubmed link
Tafuro, S., Ayuso, E., Zacchigna, S., Zentilin, L., Moimas, S., Dore, F., Giacca,
M. 2009. Inducible adeno-associated virus vectors promote functional
angiogenesis in adult organisms via regulated vascular endothelial growth
factor expression. Cardiovasc Res. 83, 663-671 Pubmed link
Collesi C, Zentilin L, Sinagra G, Giacca M. 2008. Notch1 signaling stimulates proliferation of immature cardiomyocytes. J. Cell Biol. 183, 117-128 Pubmed link
Perkins, K.J., Lusic, M., Mitar, I., Giacca, M., Proudfoot, N.J. 2008. Transcription-Dependent Gene Looping of the HIV-1 Provirus Is Dictated by Recognition of Pre-mRNA Processing Signals. Mol. Cell. 29, 56-68 Pubmed link
Sabo, A., Lusic, M., Cereseto, A., Giacca, M. 2008. Acetylation of conserved lysines in the catalytic core of CDK9 inhibits kinase activity and regulates transcription. Mol. Cell. Biol. 7, 2201-2012 Pubmed link
