Science, Technology and Engineering

Puthalakath Laboratory

Department of Biochemistry

Research - Apoptosis regulation

Puthalakath lab 2011

Bim and heart failure

Apoptosis (programmed cell death) plays a prominent role in the maintenance of tissue homeostasis. There is increasing evidence that apoptosis of cardiomyocytes was the underlying cause of a variety of heart diseases including heart failure (HF), myocarditis and ischemic heart disease. Use of βAR antagonists (or β-blockers) has had a dramatic effect on both the clinical outcomes of patients with heart failure and the progression of the underlying myocardial failure. These observations suggest that increased sympathetic activity plays an important role in the pathophysiology of HF via the stimulation of βAR. βAR are G-protein Coupled Receptors (GPCRs) and excessive stimulation of βARs (either by excessive catecholamine signalling or by autoantibodies) results in apoptosis via activation of cAMP dependent Protein Kinase A (PKA). Studies using transgenic mice with cardiac-restricted over expression of β2-AR Tg revealed cardiomyocyte apoptosis as an important change during the course of cardiomyopathy development. However, the molecular mechanism of βAR/PKA mediated cardiomyocyte apoptosis is poorly understood. Our recent studies indicate that the pro-apoptotic Bcl-2 family protein Bim is a critical regulator of cardiomyocyte apoptosis. We are currently trying to understand the regulation of Bim expression during cardiomyocyte apoptosis leading to heart failure. This is a collaborative project together with Assoc. Prof. Xiao-jun Du, Baker IDI Heart and Diabetes Institute.

Bim and Thymic negative selection

Apoptosis plays a prominent role in the maintenance of self-tolerance in the immune system. A young adult mouse with 100-200 million thymocytes generates between 20-40 million new thymocytes per day. However, the number of T cells that leave the thymus and enter the peripheral T cell pool is only about 2-3% of the number initially generated indicating that massive death must occur. Immature thymocytes are subjected to stringent selection. Thymocytes that fail to receive a signal via their T cell receptor (TCR) will undergo apoptosis (death by neglect). Only those thymocytes expressing a T cell receptor capable of interacting with peptides presented by MHC molecules with moderate affinity are positively selected and migrate to the periphery. In contrast, thymocytes with receptors that bind to self-peptide-MHC complexes with high affinity (autoreactive thymocytes) are negatively selected and undergo apoptosis. Hence negative selection ensures tolerance to normal tissues and prevents autoimmunity. Bim is a critical regulator of negative selection both in the thymus and in the periphery. We are interested in understanding the molecular mechanism of Bim regulation during negative selection. This is a collaborative project with Prof. Andreas Strasser and Dr. Philippe Bouillet at The Walter and Eliza Hall Institute.