The proposed project was designed to test important hypotheses relevant to lung physiology and pathophysiology. The long-term goal of the research plan is to isolate mechanical factors that lead to pulmonary proposed research is to investigate the effect of mechanical loading conditions applied to pulmonary arteries on the physical signals that cause degradation and synthesis of extracellular matrix components, and cellular proliferation. A general hypothetical model is proposed, relating the vascular loading forces to modes of tissues deformation (compressive, dilational, deviatoric) in the vascular tissue. Mechanisms relating tissue deformation to the biological response(degradation, synthesis and proliferation) are also proposed.
Specific aims designed to test these hypotheses are developed as part of an overall research plan. These include: (1) ex vivo and in vivo experiments on murine pulmonary arteries; (2) biological measurements of matrix degradation and synthesis and cellular proliferation; (3) development of an analytical model to predict tissue deformation modes based on tissue mechanical properties; and (4) statistical tests of the proposed hypotheses. Ex vivo perfusion allows precise control over the applied vascular forces in a near physiological environment where tissue viability is preserved where true viability is preserved. Murine pulmonary arteries will be perfused ex vivo under high pressure, high shear and hypoxic conditions (independent variables). In vivo studies present a more complex mechanical environment but allow longer-term studies to be performed. The synergistic effects of hypoxia and disrupting the nitric oxide pathway will be tested in vivo with transgenic mice (independent variables). Dependent variables describing the biological response of the tissue including global and local assays of collagenase expression and activity, elastase activity, elastin degradation, collagen deposition and cellular proliferation. Tissue deformation in measurements of residual stress and vessel geometry (wall thickness, diameter). This combined experimental and theoretical approach provides a framework a framework for future developments on the cell scale by investigating cellular transduction mechanisms, and on the full vessel scale by isolating vascular forces and deformations that lead to pathological remodeling in pulmonary hypertension.
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