Contribution of adipose tissue and liver to cachexia associated with chronic kidney disease

Descripción del proyecto

Abordar los factores metabólicos de la caquexia en la enfermedad renal

Los pacientes que padecen enfermedades crónicas suelen presentar caquexia, un síndrome metabólico grave asociado a la pérdida involuntaria de peso y al desgaste muscular. La caquexia se caracteriza por un aumento de los mediadores inflamatorios y una mayor tasa metabólica basal. Empeora el desenlace clínico y la calidad de vida de los pacientes con enfermedad renal crónica, especialmente los que reciben tratamiento renal sustitutivo. Con el apoyo de las Acciones Marie Skłodowska-Curie, el equipo del proyecto StopKidneyCachexia pretende investigar el papel de la desregulación en el tejido adiposo y el hígado en la caquexia y reducir su devastadora carga clínica. Los investigadores diseccionarán los mecanismos de la pérdida de energía sistémica, identificarán los biomarcadores tempranos y evaluarán las dianas terapéuticas en unos modelos preclínicos.

Objetivo

Cachexia is a life-threatening wasting syndrome, defined by an involuntary loss of body weight, that affects a large proportion of patients with advanced chronic diseases. Kidney diseases affect > 850 million people worldwide and represent the 10th leading cause of death. In this context, cachexia associated with chronic kidney diseases (KCx) is a huge burden in end-stage patients with kidney replacement therapies. Patients with KCx experience frailty, which worsens their quality of life (impacting their social- and professional life), hospitalization and mortality rates. So far, most research efforts have tried to identify primary pro-cachectic factors contributing to muscle wasting, but this was unfruitful in terms of therapeutics. Here, we are proposing a translational and interdisciplinary project that will focus on novel tissues (i.e adipose tissue and liver) with great relevance in the control of systemic energy metabolism. Preliminary data obtained in collaboration with the host laboratory have shown that these two tissues undergo a strong remodeling of their glucose and lipid metabolism, which could contribute to energy loss and body wasting. The main objectives of the project will be: 1) to understand the mechanisms by which altered metabolic pathways contribute to wasting in fat, liver and muscle cells; 2) to assess the biomarker potential of products of these metabolic pathways for early diagnosis of patients with KCx; and 3) to assess the therapeutic potential of targeting these metabolic pathways in mouse models of KCx. With this project, we will develop a novel research axis combining my expertise in the field of cachexia and metabolism to the expertise of the host in the field of kidney diseases. The project will be supported by highly relevant in vitro and in vivo models, access to patients’ samples, and innovative techniques. This fellowship will allow to develop my independency and to get a competitive research profile to pursue an academic career.