Dario Diviani, Professeur assistant, Privat Docent
Dario Diviani received his PhD in 1998 from the University of Lausanne for research on alpha-1 adrenergic receptors performed with Prof. Susanna Cotecchia. Between 1998 and 2001, he performed a post doctoral training with Prof. John D. Scott at the Vollum Institute of the Oregon Health Sciences University, Portland, where he worked on the molecular mechanism controlling signaling specificity in heart cells. In 2001, he joined the Department of Pharmacology of the University of Lausanne, as an independent investigator. He currently holds the position of Associate Professor.
The role of A-kinase anchoring proteins in cardiac protection
Heart failure is a lethal disease that can develop after myocardial infarction (MI), hypertension, or anti-cancer therapy. In the damaged heart, loss of function is essentially due to cardiomyocyte death and associated cardiac remodeling. Therefore, identifying relevant molecular mechanisms controlling cardiomyocyte survival under these pathological conditions could be exploited to prevent cardiac dysfunction.
The intracellular transduction events controlling cardiac these events are regulated by scaffolding and anchoring proteins, which ensure coordination of physiological and pathological signals in space and time. In this respect, we investigate how A-kinase anchoring proteins (AKAPs), a prototypical family of anchoring scaffolding proteins, tether protein kinase A (PKA) and other signaling enzymes to orchestrate and synchronize cellular processes associated with cardiac remodeling and protection.
In particular, we are taking advantage, genetically engineered mice, primary cultures of cardiomyocytes, echocardiographic and imaging approaches, and state-of-the-art molecular and cellular biology techniques, to define the role of AKAPs in the epigenetic and transcriptional processes that favor heart protection against MI-associated remodeling and the cardiotoxic effects of doxorubicin-based anti-cancer therapies.
Figure 1: Inhibition of AKAP-Lbc in cardiomyocytes causes heart failure in response to cardiac stress. Masson’s trichrome stained transversal histological ventricular sections of mouse hearts submitted to pressure overload (TAC). Left ventricular chamber dilation indicative of heart failure is observed following inhibition of AKAP-Lbc (bottom left).
Figure 2: Model illustrating the role of the AKAP-Lbc complex in the compensatory cardiac response to stress. In response to pressure overload AKAP-Lbc promotes the sequential activation of PKNα, MLTK, MKK3 and p38α within the AKAP-Lbc complex. This results in the activation of the mTOR signaling pathway that controls protein synthesis and promotes compensatory cardiac hypertrophy. This temporarily preserves the function of the stressed heart.
Rational design of molecular inhibitors of A-kinase anchoring proteins as potential anti-cancer agents.
Among the multitude of AKAPs identified so far, AKAP-Lbc has the peculiarity of being overexpressed and/or mutated in a multitude of human cancers. AKAP-Lbc acts as a guanine nucleotide exchange factor the specifically activates RhoA, a small GTPase involved in promote cell proliferation, migration and invasiveness. Tumors overexpressing AKAP-Lbc are highly invasive and display increased resistance to cancer therapy treatments. Targeting the interaction between AKAP-Lbc and RhoA in this context may constitute an attractive therapeutic approach to control tumor invasion. Using a combination of structural analysis, high throughput virtual screening of compound libraries and biochemical and cell biological screening assays we identify and characterize small molecule compounds able to inhibit AKAP-Lbc mediated prostate cancer growth and metastasis.