Major funding award for heart research from NIH
2016 Program Project Grant–Solaro, Russell, de Tombe–Integrated Mechanisms of Cardiac Maladaptation
Our program project addresses the mechanism of processes triggered by stresses on the heart that are adaptive and compensatory or are maladaptive and exacerbate the stressor, leading to decompensation, heart failure, and sudden death. The theme of our program is couched in the following hypothesis: Heart failure and sudden death commonly instigated by hypertension, coronary artery disease, and sarcomeric mutations, induce altered signaling, remodeling, and function at the level of the myofilaments–and that interventions operating at the level of the sarcomeres represent an important therapeutic approach. The program consists of three highly interactive and synergistic projects testing the overall hypothesis with diverse but meshing perspectives. Projects are supported by 3 Cores: Administrative, Human Cell and Tissue, and Proteomics and Analytical Biochemistry. Our approaches include novel mechanisms of signaling to and from the sarcomeres with a focus on translation of our findings to therapies for acquired and genetic cardiomyopathies.
Dr. Russell leads Project 2, entitled Mechano-Feedback Signaling and Sarcomere Assembly, which proposes innovative experiments using microstructures of varying stiffness in testing the hypothesis that sarcomeric actin assembly depends on posttranslational modification (PTM) of proteins regulated by external cues signaling via mechano-transduction pathways. The experiments employ bioengineered micro-rods and magnetic micro-magnets to establish baseline values and then test whether specific mechanisms of local actin assembly are via interaction of PKC-ε, HDAC3, and PIP2 with the actin capping protein, CapZ.