Inter-organ crosstalk can be defined as the complex multidirectional communication between distant organs by signaling factors that act as autocrine, paracrine, or endocrine mediators to regulate whole-body homeostasis. This implies that chronic dysfunction in one organ leads to dysregulation of other organs. Indeed, chronic inflammatory and metabolic diseases such as obesity, type 2 diabetes, non-alcoholic fatty liver disease, and cutaneous and neuro-inflammatory conditions, feature alterations in the inter-organ crosstalk. The inappropriate release of inflammatory mediators including cytokines, hormones, and growth factors, often leads to organ dysfunction or disease, and constitute the main focus of this proposal. In this project, we will address metabolic dysfunction and neuropathologies, with particular emphasis on the interactions between peripheral organs (white adipose tissue and liver), the central nervous system, and the skin.
Our main global objective is to achieve deeper understanding of inter-organ networks in order to facilitate early diagnosis of the disease, improve short- and long-term therapeutic strategies, and promote healthy living and aging.
The specific project aims are: 1) identify systemic and tissue-specific secreted factors involved in inter-organ crosstalk in metabolic dysfunction and neuro-inflammation/neuro-degeneration; 2) mechanistic and functional studies; and 3) validation of selected candidate factors and development of targeted therapies as proof-of-concept for their use as biomarkers and/or treatment. A wide range of methodological approaches will be used including: i) an experimental protocol mimicking the metabolic syndrome – high-fat diet as paradigmatic example– in combination with genetically modified mice that are either protected or more prone to develop clinical manifestations of the disease; ii) combined metabolomic and transcriptomic profiling approaches; iii) cellular models of corresponding pathologies (2D and 3D); and iv) human iPSC-derived cells and organoids. Feasibility of the project is supported by the long standing record, complementary expertise, and shared common interests of this multidisciplinary team in the study of molecular mechanisms underlying chronic inflammatory and metabolic diseases. Successful completion of the objectives of the current proposal will expand the understanding of the molecular basis of inter-organ crosstalk and may potentially identify new druggable targets that would reduce the economic burden of these diseases.