Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - NutrientSensingVivo (The Physiology of Nutrient Sensing by mTOR)

Teaser

This project aims to understand the cellular responses to fluctuations in nutrient levels, and how perturbations in nutrient levels or in the detection and signaling affect cellar and systemic metabolic decisions and human disease. The alarming increase in nutrient intake...

Summary

This project aims to understand the cellular responses to fluctuations in nutrient levels, and how perturbations in nutrient levels or in the detection and signaling affect cellar and systemic metabolic decisions and human disease.

The alarming increase in nutrient intake, sedentarism and obesity calls for a better understanding of the molecular underpinnings of the cellular and organismal responses to such energetic perturbations. This would allow prevention and treatment strategies targeting the aberrant signaling of nutrients in human diseases such as cancer and diabetes.

Our objectives include the understanding of how are the intracellular and extracellular nutrient levels sensed and how are the responses orchestrated. We combine signal transduction information with physiology learned by the means of mouse genetics to provide a complete vision from the molecule to the organismal coordinated responses.

Work performed

We have analyzed what are the metabolic consequences of a constitutive signal of cellular nutrient abundance. We found that the sole signal of increased nutrient levels unleash aberrant metabolic responses and alterations consistent with a prediabetic state, including elevated glycaemia, insulin resistance and deregulated levels of other nutrients in the circulation (see figure). This occurs without manipulating the actual energetic intake, only the cellular signals that arise when nutrient levels are elevated. We have started to dissect, with specific genetic tools, the contribution of different organs (liver, skeletal muscle) to these metabolic defects observed in mice where every cell has this signaling perturbation. We have also determined that a chronically high signaling cascade of nutrients generates defects consistent with an imbalance in the components of the protein synthesis machinery of the cell. We have generated new tools to study how and why deregulated nutrient signaling drives certain human cancers, such as lymphomas, and established the reasons by which nutrient signaling affects B lymphocytes in particular (see figure). In addition, these novel tools revealed that an increase in nutrient signaling corrupts the internal control of B lymphocytes that prevent autoimmunity. We have identified novel potential players involved in the response to high nutrient levels that control the most energetically-demanding process in the cell, that is the synthesis of proteins.

Final results

We expect to provide the first formal proof of the oncogenicity of the nutrient signaling cascade, by understanding its deregulation of B lymphocyte function. In this context, we will evaluate the impact of dietary manipulations, including caloric restriction, to cells and tumors that hijacked the nutrient signaling cascade to foster aberrant growth and proliferation. We also intend to establish a proof-of-concept scenario for targeting the nutrient signaling cascade as an anticancer strategy. Our results have also fostered our interest in determining the connection between nutrient levels and the onset of autoimmune pathologies.
We intend to understand in a per-organ basis, the metabolic perturbations associated with high nutrient signaling in the absence of an actual perturbations in nutrient intake or levels. And to ascertain to what extent the metabolic and developmental alterations observed in mice with deregulated nutrient signaling are caused by an aberrant control in the synthesis of proteins.
Based on unbiased proteomic screens that we have conducted in the lab, aiming at the identification of factors that are regulated by nutrient signaling, we also intend to determine the relevance of nutrients in the post-translational control of a family of proteins that are frequently altered in colorectal carcinoma.