FOR 2036:  New Insights into Bcl-2 Family Interactions: From Biophysics to Function

• Subject Area: Medicine ; Biology
• Term: from 2014 to 2022
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 232935877

Bcl-2 family proteins are core regulators of the intrinsic pathway of apoptosis, acting on mitochondria through complex interactions within the family. Thus, an intricate insight into their regulation is highly important for understanding physiology and disease and for creating novel treatment paradigms. Indeed, small molecules inactivating anti-apoptotic Bcl-2 proteins effectively kill cancer cells and have entered phase-II/III clinical trials. In fact, April 11th 2016 marks the first FDA approval for one of these compounds.While the field of apoptosis and Bcl-2 family research has arrived at the bedside, there is a distinct lack of knowledge on a number of critical issues. Our consortium has helped to gain relevant ground on some of these issues and aims to address questions, unanswered in the field, in a highly collaborative approach in 3 work packages (WP). WP1: Despite a basic understanding of apoptosis, the real ordering of events for cell death execution within the Bcl-2 family is still relevantly unclear. WP1 will address the role of stochiometry, complex formation, membrane interaction and post-translational control of Bcl-2 family interactions with advanced methodology, ranging from advanced microscopy investigations into biophysical properties to sophisticated protein chemistry.WP2: The limited knowledge on the interaction between Bcl-2 regulated apoptosis and other cell death or proliferative pathways connects to relevant clinical questions. WP2 will elucidate interactions of the Bcl-2 family with cell cycle and the death receptor pathway, and will explore currently uncharted cellular stress responses in biologically relevant models. Approaches include cell biology assays on primary tissues, mitotic cell death analysis and modelling approaches integrating data spanning biophysics to cell biology.WP3: The exciting FDA-approval of a first-in-class Bcl-2 inhibitor pairs with a critical shortage of essential knowledge for further development of these drugs. In fact, early insights into toxicities, the lack of clear knowledge on resistance mechanisms and relevant biomarkers impede treatment success. In WP3 clinician scientists tackle such questions by establishing Bcl-2 family expression profiles from unique clinical sample sets and bridging functional questions into disease models. Maps of clinical materials will connect to interventional mouse models allowing important insights into CLL, AML/MDS and unique paediatric tumors.Next to the proven track-record of collaboration of the group the proposal contains extensive crosstalk within and between work packages ensuring a continued high output in terms of discovery and translational potential. We expect to gain relevant ground on a number of unanswered questions, critical for understanding the basic biology of cell death and clinical development in a number of diseases.

• DFG Programme: Research Units
• International Connection: Austria, Switzerland

Projects

• Bcl-2 family members in microenvironmental support in Chronic Lymphocytic Leukemia (Applicant Egle, Alexander )
• Characterization of BOK in hematopoietic stem/progenitor cell fitness, stress response and leukemic transformation (Applicant Jost, Philipp )
• Characterization of pro- and anti-apoptotic Bcl-2 proteins regulating hematopoiesis and leukemogenesis in the context of RAS hyperactivation (Applicant Erlacher, Miriam )
• Coordination Funds (Applicant Brunner, Thomas )
• Defining the role of BH3-only proteins in mitotic and post-mitotic cell death (Applicant Villunger, Andreas )
• Identifying binding partners and molecular functions of the Bcl-2 family member Bok (Applicant Kaufmann, Thomas )
• Molecular activation and activity of the BH3-only protein Bim (Applicant Häcker, Georg )
• Role of the Bcl-2 family and TRAIL signaling in paracetamol-induced necrosis in liver cells (Applicant Brunner, Thomas )
• Signal integration by phosphorylation and complex formation of Bim and Puma (Applicant Borner, Christoph )
• Stoichiometry of homo- and hetero-complexes of Bcl-2 proteins at the single molecule level (Applicant Garcia Sáez, Ana Jesús )
• Systems biological analysis of mitochondrial apoptosis synergies evoked by 2nd generation TRAIL receptor agonists and cardic glycosides (Applicant Morrison, Markus )

• Spokesperson: Professor Dr. Thomas Brunner