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Research Interests
Elucidation of the Cellular and Molecular Mechanisms Involved in the
Brain Angiotensin Control of Cardiovascular Functions:
Our studies have established that the brain Renin-Angiotensin System (RAS) is key in the control
of blood pressure and other cardiovascular functions. This view is further
supported by the fact that the expression and activity of this system is
enhanced in hypertension. Our laboratory has been involved in elucidating the
cellular and molecular mechanisms of the brain Ang-II action in the brain in
order to develop a better therapeutic strategy for its hyperactivity and thus
devise novel ways to control hypertension.
The following lines of investigations are underway in this study:
- Studying the signal transduction mechanism of Ang II-induced
Norepinephrine (NE) neuromodulation. The role of various kinases
such as MAPK, PI-3K, PKC, and CAMK on Ang-II induced vesicular trafficking,
NE release, and synthesis are being investigated.
- Mechanisms of Ang II-regulated NE neuromodulation in the
neurons of the SHR is being investigated. The hypothesis that the AT1
receptor is coupled to two distinct signaling pathways in the SHR neurons is
being investigated.
- Gene profiling techniques are being used to identify known
and unknown genes that are regulated by Ang-II in the brain. In addition,
efforts are underway to identify hypertension related genes. A number of such genes have been identified
from the hypothalamus and studies are underway to identify and determine their
functions.
Genetic Targeting of the RAS for the Control of Hypertension:
Our previous studies have established that a single intracardiac injection of a
retroviral vector containing either AT1 receptor antisense cDNA or ACE-antisense cDNA prevents
animals from developing hypertension for life. This is an exciting observation
and provides conceptual support that antisense targeting of the RAS could be an
important strategy for the long-term control of hypertension.
The following lines of investigation are underway in this area:
- Provide further conceptual support for antisense gene
therapy by using many different models of hypertension
- Use lentiviral-based vectors to determine a long-term
reversal of hypertension
- Explore the possibility of using tissue/cell specific
promoters to drive the expression of antisense and determining the role of
tissue RAS in hypertension.
- Develop a tet-regulated AT1R-AS expression
system for in vivo use. Our objective is to "turn-on"
and "turn-off" the expression of AT1R-AS in-vivo on demand
and study its effects on hypertension.
- The cardiovascular-protective role of the AT2 receptor is being
investigated. We are testing the hypothesis that overexpression of
this receptor may protect animals from hypertension.
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