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The focus of this laboratory is to study the effect of cigarette smoke exposure in cardiovascular and renal diseases. Despite global efforts to decrease the tobacco related atherosclerosis burden, this remains a major public health problem. Strategies to assist with withdrawal of tobacco have only been sparsely successful leading to an increasing incidence of tobacco associated coronary artery disease and its consequences.
Our investigations will serve to pave the way for clinical studies of new biomarkers specific to tobacco smoke risk ascertainment, provide insight toward novel targets of therapy and open the door for the conduct of clinical trials in the setting of chronic atherosclerosis as well as during acute coronary syndromes that seek to ameliorate tobacco related inflammation, immune aberrations and oxidative stress.
Inflammation and oxidative stress are considered central to the genesis of atherosclerosis, a leading cause of death in the modern world. Tobacco use has been established as an important risk factor in the development and progression of atherosclerosis but the fundamental mechanisms linking smoking to atherosclerosis remain poorly elucidated. Since tobacco exposure may result in increased inflammation, altered immunity, and heightened oxidative stress, we perform studies with a mice model of atherosclerosis that simulates the human model, by exposing them to tobacco smoke. Since the comprehensive and longitudinal exploration of this phenomenon will be difficult in humans, the proposed mouse model will provide the best alternative. We investigate the influence of smoking tobacco on alterations in the immune system, inflammatory and pro-proliferative factors as well as their relationship to the genesis of atherosclerosis.
Additionally, we perform experiments to attenuate these harmful effects of tobacco smoke using statins. If these agents demonstrate promising beneficial results in reversing the deleterious effects of tobacco smoke on atherosclerosis, newer prophylactic strategies will be developed clinically to control tobacco smoke mediated development of atherosclerosis and decrease the overall burden of this vexing clinical dilemma.
Cigarette smoking is one of the most avoidable risks in health and disease. It is known to be one of the causes for progression of cancer, cardiovascular and chronic kidney diseases. It is also believed to be responsible for decreased quality of life of organ transplant recipients. The precise contribution of smoking in the development of allograft rejection and nephropathy as well as the underlying molecular mechanisms has not been well explored.
Additionally, the pharmacological effects of smoking in the presence of immunosuppressive drugs remain to be elucidated. Smoking is also responsible for increased inflammation and oxidative stress, known to participate in allograft rejection and allograft nephropathy. Oxidative stress may be responsible for 1) early graft failure by increasing inflammation by polymorphonuclear cells infiltration and cytokine induction; 2) nephrotoxicity through increased expression of TGF-beta and extracellular matrix proteins. Thus, there is an imperative to thoroughly investigate downstream effecter pathways that can be influenced to block the deleterious effects of tobacco smoke on the renal function, allowing for the development of newer strategies to treat transplant recipients.
The following studies are being conducted:
Our studies have shown that cyclosporine (CsA), tacrolimus (TAC) and sirolimus (SRL) induce expression of transforming growth factor beta (TGF-β). It is likely that the inhibition of lymphocyte proliferation by CsA, TAC and SRL may be due in part, to the subsequent induction of cyclin inhibitor p21 by TGF-β signaling pathways. We have demonstrated that overexpression of p21 in vitro and in vivo render lymphocytes less responsive to allo-and mitogen-induced proliferation and p21 overexpression prolongs allograft survival in rat heart transplant recipients. Since p21 is a potent inhibitor of lymphocyte proliferation, and appears to be a key mediator of the immunosuppressive effects of CsA, TAC, and SRL, our hypothesis is that p21 may be useful as an immunosuppressive agent to inhibit transplant rejection.
Studies that we and others have reported have also shown that TGF-β signaling induced by long-term treatment with CsA, TAC, or SRL regulate the expression of a variety of genes that contribute to the development of harmful and frequent side-effects, such as nephrotoxicity. However, it is significant that the TGF-β signaling pathways that contribute to the development of nephrotoxicity apparently do not involve p21. Thus, our second hypothesis is that the narrower range of effects mediated by p21 will result in fewer or less severe side-effects than those caused by CsA, TAC, or SRL.
Our interest in developing p21 as an immunosuppressive therapeutic was enhanced by our discovery that, remarkably, exogenously supplied recombinant p21 protein can pass directly into lymphocytes, enter their nuclei, and interact with transcription factors that regulate immune response genes. This unusual property of p21 is apparently due to the presence of a naturally occurring protein transduction domain (PTD) in p21 that resembles the well-characterized PTD of the HIV Tat protein. Due to its unique properties, we believe that recombinantly expressed p21 may be suitable for use as a therapeutic without the need for amino acid sequence modifications, unusual formulation methods, or gene-therapy approaches.
We perform studies to test the feasibility of using p21 protein as a novel therapeutic to prevent organ transplant rejection. Our studies consists of in vivo dose-ranging studies in rats to determine the highest dose of recombinant p21 protein that inhibits of lymphocyte proliferation without causing significant (if any) toxicity. The other studies are to compare p21 and a widely used immunosuppressant, CsA, in rat heart and kidney transplant models for efficacy and toxicity. We believe that two significant outcomes of p21 therapy will be: 1) a comparable or superior allograft survival rate relative to CsA, and 2) a significant reduction or elimination of nephrotoxicity and other side-effects relative to those that are observed when CsA, TAC, or SRL. Evidence to test these hypotheses will be obtained via the studies proposed in this application.
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