Sharma Gaurav, Kulkarni Rohan, Shah Samir K, King William W, Longchamp Alban, Tao Ming, Ding Kui, Ozaki C Keith (2016), Local perivascular adiponectin associates with lower extremity vascular operative wound complications., in Surgery
, 160(1), 204-10.
Allagnat F, Haefliger J-A, Lambelet M, Longchamp A, Bérard X, Mazzolai L, Corpataux J-M, Déglise S (2016), Nitric Oxide Deficit Drives Intimal Hyperplasia in Mouse Models of Hypertension., in European journal of vascular and endovascular surgery : the official journal of the European Society
, 51(5), 733-42.
Longchamp Alban, Allagnat Florent, Alonso Floriant, Kuppler Christopher, Dubuis Celine, Ozaki C. Keith, Mitchell James R., Bercelli Scott, Corpataux Jean-Marc, Deglise Sebastien, Haefliger Jacques-Antoine (2015), Connexin43 Inhibition Prevents Human Vein Grafts Intimal Hyperplasia., in Plos One
Sharma Gaurav, Tao Ming, Ding Kui, Yu David, King William, Deyneko Galina, Wang Xiaosong, Longchamp Alban, Schoen Frederick J, Ozaki C Keith, Semel Marcus E (2015), Perivascular adipose adiponectin correlates with symptom status of patients undergoing carotid endarterectomy., in Stroke; a journal of cerebral circulation
, 46(6), 1696-9.
Longchamp Alban, Tao Ming, Bartelt Alexander, Ding Kui, Lynch Lydia, Hine Christopher, Corpataux Jean-Marc, Kristal Bruce S., Mitchell James R., Ozaki C. Keith (2015), Surgical injury induces local and distant adipose tissue browning, in Adipocyte
In this proposal, we propose to test the hypothesis that short-term protein restriction attenuates IH by reducing secretion of the proinflammatory adipokine leptin, via inhibition of the nutrient/energy sensor mTORC1 specifically in adipocytes. This proposal builds on my mentors established murine model of IH (carotid artery focal stenosis), published expertise in vascular biology, protein/amino acid sensing and dietary interventions. This hypothesis will be tested via the following Specific Aims:Aim 1. Establish leptin as the molecular link between protein restriction and protection from IH. Our data indicate that protein restriction 1) reduces systemic leptin levels, and 2) reduces IH after carotid stenosis. Because leptin exacerbates IH, we propose to test the hypothesis that there is a causal relationship between reduction of leptin levels upon protein restriction and prevention of IH. To this end, we will use our validated murine carotid stenosis model, in mice preconditioned on a protein-restricted diet with or without addition of exogenous leptin. We predict protein restriction-mediated protection from IH will be lost upon exogenous leptin administration.Aim 2. Establish the nutrient/energy sensor, mTORC1, as the key positive regulator of leptin production in adipocytes. Leptin is a hormone produced primarily by adipocytes in response to nutrient/energy levels. mTORC1 integrates signals from amino acid, energy and growth factor availability to impact cellular decisions on anabolic and catabolic processes. We propose that the reduction in leptin observed upon short-term protein restriction depends on reduced mTORC1 signaling specifically in adipocytes. We will test this in differentiated adipocytes in vitro using short hairpin RNA targeting a negative regulator of mTORC1 (Tsc1), and in vivo using a genetic mouse model in which Tsc1 is ablated specifically in adipocytes (ATsc1KO) resulting in mTORC1 overactivation. We predict that upon adipose mTORC1 overactivation 1) leptin levels will be increased independently of food intake and 2) mice on a protein-restricted diet will loose protection against IH.