· Vascular response to injury and disease
· Vascular smooth muscle (VSM) cell biology; Regulation of VSM phenotype and function
· Calcium signaling mediated by multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII)
Vascular smooth muscle is the principal (by mass) cellular component of the blood vessel wall and in its quiescent differentiated state contracts and relaxes to adjust blood pressure and flow. Hypertrophic growth and proliferation of VSM contributes to chronic hypertension, a major risk factor for heart disease and stroke. VSM is not terminally differentiated and a characteristic property of this cell is reversible de-differentiation resulting in a “synthetic” phenotype that proliferates, migrates and produces extracellular matrix. The transition from contractile to synthetic phenotypes is stimulated by environmental stimuli and growth factors produced in response to injury and disease and the synthetic phenotype VSM is a key component of occlusive vascular proliferative diseases, including atherosclerosis. Thus, VSM is a key component of, and potential therapeutic target for, pervasive cardiovascular diseases.
Ca2+ is an essential intracellular second messenger in virtually all cells and participates in control of diverse cellular processes including muscle contraction, gene transcription, cell growth and motility. One ubiquitous but poorly understood mediator of Ca2+ signals is the multifunctional serine/threonine protein kinase, Ca2+/calmodulin-dependent protein kinase II (CaMKII). This laboratory has been instrumental in discovering new forms of CaMKII that are variably expressed in all cells and tissues and we are engaged in understanding the relationship between the complexities of CaMKII structure and specific cellular functions. We have developed an extensive set of biochemical tools, imaging approaches (live cell, confocal immunofluorescence, and TIRF microscopy), molecular mutants, and most recently genetic mouse models to assess CaMKII function, particularly in VSM.
Our immediate research goals are to:
1) determine the function of CaMKII isoforms in regulating vascular injury-induced VSM cell phenotype switching;
2) determine the function of CaMKII isoforms in regulating specific transcriptional regulatory pathways
3) visualize subcellular targeting of CaMKII isoforms and assess function as a mediator of localized Ca2+ signaling controlling VSM cell motility
4.) determine mechanisms of localized CaMKII activation in specific subcellular compartments and function in VSM polarization and directional motility