Line 1. Caveolin-1 as a negative regulator of HIF-1α in cancer. (PI: A. Quest)
In the first part of this project, Caveolin-1 function in the context of cancer will be studies. Caveolin-1 is widely considered a tumor suppressor, whereby downregulation of β-catenin/Tcf-Lef dependent transcription of cancer genes is viewed as a possible mechanistic explanation. However, Caveolin-1 function as a tumor suppressor was observed in cells lacking E-cadherin. In solid tumors, the increased imbalance between oxygen supply and demand due to insufficient vascularization, activates the hypoxia-induced factor 1 (HIF1). Recent evidence suggests that HIF1α target gene expression is increased in caveolin-1 knock-out mice. Furthermore, caveolin-1 absence in the tumor stroma is associated with enhanced oxidative stress due to mitochondrial malfunction in hypoxia and increased expression of genes involved in glycolysis. Based on these observations we propose to explore here whether caveolin-1 expression modulates HIF1α transcriptional activity in tumor cells.
Line 2: Regulation of macroautophagy and chaperone-mediated autophagy in cardiac myocytes. (PI: S. Lavandero)
In the heart, IGF-1 increases protein synthesis and reduces protein degradation. Insulin regulates cardiac growth and metabolism. In cardiac muscle, increased protein synthesis is associated with heart hypertrophy. Moreover, physiological hypertrophy also involves the regression of cardiac cell growth probably through a controlled protein degradation mechanism. Protein degradation in cardiac muscle is mediated by both the lysosomal pathway and the ubiquitin–proteasome pathway. Macroautophagy and chaperone-mediated autophagy (CMA) are two well-known lysosomal pathways of protein degradation. Both macroautophagy and CMA are up-regulated in response to different inducers of stress, including starvation/nutrient deprivation, hypoxia, reactive oxygen species (ROS), damaged organelles and protein aggregates. Our goal is to determine whether stress-induced Ca2+/ROS signaling triggers macroautophagy and chaperone-mediated autophagy in cardiomyocytes, and whether both processes are prevented by insulin and/or IGF-1.
Line 3: Skeletal muscle response to lipotoxicity involves extracellular ATP and reactive oxygen species, leading to insulin resistance. (PI: E. Jaimovich)
In skeletal muscle ATP, a molecule considered for a long time as an energy source, regulates proliferation, differentiation and regeneration and also promotes stabilization of the neuromuscular junction. We have described that ATP released by electrical stimuli triggers calcium transients and gene expression. The mechanism by which extracellular ATP regulates gene expression and the role of extracellular ATP in glucose homeostasis, as well as events other than the regulation of gene expression are poorly understood. We propose that the signaling processes activated by ATP release are involved in adult muscle plasticity. Therefore, our goal is to determine whether ATP released by the muscle cell under physiological stimuli is an important autocrine signal which regulates both muscle gene expression and metabolism.
Line 4: Stress-induced intraorganelle communication. (PI: S. Lavandero)
Communication proves to be a key prerequisite for the most cell-based life-forms. Most eukaryotic cells contain a variety of membrane-limited organelles and often organelle function is coordinated by communication via membrane contact sites formed upon juxtapositioning of the respective organelles. The molecular machinery involved in the formation and regulation of these structures, as well as determining their precise function remain largely unknown. We will evaluate whether increased ER-mitochondria communication following inhibition of mTOR by rapamycin requires the participation of Herp and caveolin-1, and whether IGF-1 receptor signaling is compartmentalized in plasma membrane invaginations which form microdomains associated with the nuclear envelope.
Line 5: Lipotoxicity/Insulin resistance in heart and pancreatic β-cells. (PI: A. Quest)
Lipid accumulation in the heart, skeletal muscle, pancreas, liver, and kidney is associated with heart failure, obesity and type 2 diabetes mellitus (T2DM). This process, referred to as lipotoxicity, accounts for many facets attributed to the “metabolic syndrome”. Lipotoxicity associated with elevated free fatty acid (FFA) levels is considered one of the most relevant factors associated with insulin resistance and loss of β-cell viability. Mechanisms by which FFAs provoke these changes in TDM2 will be evaluated in experiments involving all three PIs.
Line 6: Stress-induced muscle wasting. (PI: E. Jaimovich)
Muscle atrophy, also known as muscle wasting, is a debilitating syndrome that slowly develops with age (sarcopenia) or rapidly appears in late stages of deadly diseases, such as cancer and sepsis (cachexia). The molecular mechanisms of sarcopenia and cachexia have just begun to be elucidated. We will evaluate whether different stimuli, such as ROS and glucocorticoids, can regulate autophagy in skeletal muscle and its involvement in muscle atrophy
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