zes the research and career plan proposed by Dr. Gerald D. Frank, which focuses on uncovering novel vascular signaling pathways and mechanisms utilized by protein kinase C (PKC) delta activated by vascular pathogens that lead to vascular remodeling. Identifying key PKC delta activation mechanisms and its precise signaling sequence involved in the vascular remodeling process is very important for understanding development of vascular diseases and establishing new strategies and therapies toward PKC delta-dependent vascular signaling and function activated by vascular pathogeng. A critical component of vascular diseases may involve intracellular mechanisms. Vascular pathogens such as angiotensin II, platelet-derived growth factor and reactive oxygen species activate key protein kinases promoting cell growth and migration of vascular smooth muscle cells (VSMCs), thereby contributing to the development of cardiovascular diseases. It is likely that key signal transduction cascades involved in functional responses to vascular pathogens converge at the level of PKC activation since it is one of the earliest signaling events induced by them. We have shown that PKC delta is linked to the activation of various tyrosine kinases in VSMCs. Therefore we hypothesized that PKC delta acts as a unique signal sensing molecule and is required for activation of specific downstream signal transductions in VSMCs critical for vascular remodeling.
Specific Aim #1 of this application is to determine the molecular mechanism responsible for integrated PKC delta activation induced by key vascular pathogens in cultured VSMCs.
Specific Aim #2 is to determine the pathogen-induced protein-protein interactions of PKC delta with various signaling molecules in VSMCs and to identify the critical downstream signal transduction of PKC delta.
Specific Aim #3 will determine the functional downstream role(s) of PKC delta activation essential for VSMC growth and migration. This research will utilize various new experimental methodology and expertise in biochemistry, physiology, vascular biology, structural biology and cell and molecular biology. The Biochemistry Department at Vanderbilt University School of Medicine is an excellent and ideal institution to develop the independent academic career of the applicant whose long-range goal is to elucidate the activation mechanisms and functions of specific PKC isoforms in VSMCs underlying development of vascular remodeling.
|Hinoki, Akinari; Kimura, Keita; Higuchi, Sadaharu et al. (2010) p21-activated kinase 1 participates in vascular remodeling in vitro and in vivo. Hypertension 55:161-5|
|Nakashima, Hidekatsu; Frank, Gerald D; Shirai, Heigoro et al. (2008) Novel role of protein kinase C-delta Tyr 311 phosphorylation in vascular smooth muscle cell hypertrophy by angiotensin II. Hypertension 51:232-8|
|Ohtsu, Haruhiko; Higuchi, Sadaharu; Shirai, Heigoro et al. (2008) Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells. Endocrinology 149:3569-75|
|Higuchi, Sadaharu; Ohtsu, Haruhiko; Suzuki, Hiroyuki et al. (2007) Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 112:417-28|
|Nakashima, Hidekatsu; Suzuki, Hiroyuki; Ohtsu, Haruhiko et al. (2006) Angiotensin II regulates vascular and endothelial dysfunction: recent topics of Angiotensin II type-1 receptor signaling in the vasculature. Curr Vasc Pharmacol 4:67-78|
|Ohtsu, Haruhiko; Dempsey, Peter J; Frank, Gerald D et al. (2006) ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II. Arterioscler Thromb Vasc Biol 26:e133-7|
|Suzuki, Hiroyuki; Frank, Gerald D; Utsunomiya, Hirotoshi et al. (2006) Current understanding of the mechanism and role of ROS in angiotensin II signal transduction. Curr Pharm Biotechnol 7:81-6|
|Suzuki, Hiroyuki; Eguchi, Kunie; Ohtsu, Haruhiko et al. (2006) Activation of endothelial nitric oxide synthase by the angiotensin II type 1 receptor. Endocrinology 147:5914-20|
|Suzuki, Hiroyuki; Motley, Evangeline D; Frank, Gerald D et al. (2005) Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement. Curr Med Chem Cardiovasc Hematol Agents 3:305-22|
|Frank, Gerald D; Eguchi, Satoru; Motley, Evangeline D (2005) The role of reactive oxygen species in insulin signaling in the vasculature. Antioxid Redox Signal 7:1053-61|
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