Cachexia is a complex syndrome characterized by massive loss of body weight due to uncontrolled loss of adipose tissue and skeletal muscle. The wasting occurs during late stages of many unrelated chronic diseases and frequently leads to the death of affected individuals. Cachexia is most common in cancer, where an estimated 25% of patients die from cancer-associated cachexia (CAC) rather than from the cancer. Despite the tremendous impact of CAC on morbidity and mortality, the underlying molecular mechanisms are poorly understood.
Recently, we demonstrated that lipase-catalyzed triacylglycerol (TG) catabolism is required for the pathogenesis of CAC. Mice lacking adipose triglyceride lipase, the rate-limiting enzyme for TG hydrolysis (lipolysis), were completely protected from loss of both adipose tissue and muscle in two forms of cancer. This implies an essential role of the lipolytic process in the pathogenesis of CAC. Here we propose to elucidate the causal role of lipases and their coregulators in CAC development. We will determine mechanisms involved and pursue novel treatment strategies.
Our objectives are to:
- Investigate how different cancers in mice regulate tissue-specific lipolysis;
- Elucidate the functional role of lipases and their coregulators in the pathogenesis of CAC;
- Assess whether pharmacological inhibition of specific lipases prevents or delays CAC;
- Study the effects of cancer-induced lipolysis on energy dissipating pathways and epigenetic control.
The project enters a largely unexplored field: the role of lipid metabolism in the pathogenesis of CAC. The work will heavily rely on the characterization of induced mutant mouse models with CAC and require extensive collaboration with experts in pathology and large-scale systems analytics. The results are expected to yield new mechanisms of disease development and provide novel therapeutic targets to prevent the devastating and prevalent consequences of CAC.
Field of science
- /medical and health sciences/basic medicine/pathology
- /social sciences/sociology/demography/mortality
- /medical and health sciences/clinical medicine/oncology/cancer
- /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes
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