Research objectives and content
OB protein, (also known as leptin), a previously unknown protein signal, is secreted from adipose tissue, circulate in the blood, probably bound to a family of binding proteins and acts on central neural networks that regulate ingestive behavior and energy balance. Leptin exerts its biological effect through its receptor (OB-R) belongs to the hematopoyetin/cytokine receptor superfamily class I. After the cloning of this receptor, occurred only one year ago, only a few studies have attempted to elucidate the signal transduction pathways of this receptor. For these reason there are numerous important questions remaining about the role of OB-R; moreover the knowledge of intracellular molecules that mediate signal transduction via OB-R are of tremendous interest. Our target in this project will be to highlight different aspects of the OB-R signaling determining alternatives to the initial JAK-Stat pathway in order to find connections with other intracellular mechanisms and also to define which of these signals, or as yet unidentified signals, is most important in body weight regulation.
Our attention will be focused on: 1- Studies on alternative JAK-STAT pathways involved in OB-R signal transduction. Our aim is to demonstrate that Insulin Receptor Substrate-1 (IRS-l) and Phosphatydilinositol 3'-kinase (PI-3' kinase) are associated with OB-R and also if there is an activation of these two proteins through phosphorylation upon leptin binding. 2- Studies on identification of OB-R sequences involved in the signaling 3- Studies on the SHC-GRB2-SOS and RAS pathway probably involved in the OB-R signalling.
Training content (objective, benefit and expected impact) The discovery and rapid characterization of the OB protein signal pathways could be significant for several reasons. First, it could provide additional evidences that obesity is a disease with a biological basis. Second, the rapid evolution of the OB protein pathway could provide a series of important advances in the knowledge base of obesity. This increasing knowledge base should help to pry open and shine a bright light onto the very dark 'black box' that contains the mechanisms and decision rules used in the brain for determining the level at which body fat content is regulated in humans and other animals. When these mechanisms will be understood at the molecular level, target identification for discovery and development of new, safe, effective pharmacological treatment for obesity could reduce risk factors and promote improved health of obese individuals. Knowing the OB-R signal transduction pathway will certainly be the primary objective of the obesity research, moreover these new knowledge will greatly expand our understanding of the development, maintenance and treatment of obesity and it should certainly provide additional hope for the many obese individuals. Additonally, the intracellular molecules that mediate signal transduction via OB-R are of tremendous interest. Although an understanding of some OB-R signal transduction capabilities is under way, it is critical to define which of these signals, or as yet unidentified signals, is most important in pathophysiology of obesity. Links with industry / industrial relevance (22)