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SAINT LOUIS, MO, United States

Hou W.-H.,Saint Louis University | Liua I.-H.,Saint Louis University | Huang S.S.,Auxagen, Inc. | Huang J.S.,Saint Louis University
FEBS Letters | Year: 2012

CRSBP-l/LYVE-1 ligands (PDGF-BB, VEGF-A 165 and hyaluronic acid) have been shown to induce opening of lymphatic intercellular junctions in vitro and in vivo by stimulating contraction of lymphatic endothelial cells (LECs). The mechanism by which CRSBP-1 ligands stimulate contraction of LECs is not understood. Here we demonstrate that CRSBP-1 is localized to the plasma membrane as well as intracellular fibrillar structures in LECs, including primary human dermal LECs and SVEC4-10 cells. CRSBP-1-associated fibrillar structures are identical to the ER network as evidenced by the co-localization of CRSBP-1 and BiP in these cells. CRSBP-1 ligands stimulate contraction of the ER network in a CRSBP-1-dependent and paclitaxel (a microtubule-stabilizing agent)-sensitive manner. These results suggest that ligand-stimulated ER contraction is associated with ligand-stimulated contraction in LECs. © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Source


Chen C.-L.,Saint Louis University | Tetri L.H.,Saint Louis University | Neuschwander-Tetri B.A.,Saint Louis University | Huang S.S.,Auxagen, Inc. | Huang J.S.,Saint Louis University
Journal of Nutritional Biochemistry | Year: 2011

Dietary trans fats (TFs) have been causally linked to atherosclerosis, but the mechanism by which they cause the disease remains elusive. Suppressed transforming growth factor (TGF)-β responsiveness in aortic endothelium has been shown to play an important role in the pathogenesis of atherosclerosis in animals with hypercholesterolemia. We investigated the effects of a high TF diet on TGF-β responsiveness in aortic endothelium and integration of cholesterol in tissues. Here, we show that normal mice fed a high TF diet for 24 weeks exhibit atherosclerotic lesions and suppressed TGF-β responsiveness in aortic endothelium. The suppressed TGF-β responsiveness is evidenced by markedly reduced expression of TGF-β type I and II receptors and profoundly decreased levels of phosphorylated Smad2, an important TGF-β response indicator, in aortic endothelium. These mice exhibit greatly increased integration of cholesterol into tissue plasma membranes. These results suggest that dietary TFs cause atherosclerosis, at least in part, by suppressing TGF-β responsiveness. This effect is presumably mediated by the increased deposition of cholesterol into cellular plasma membranes in vascular tissue, as in hypercholesterolemia. © 2011 Elsevier Inc. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 182.19K | Year: 2008

DESCRIPTION (provided by applicant): Diabetes mellitus afflicts 20.8 million people, or 7% of the population, in the United States. Fifteen percent, or 2.4 million people, will develop diabetic foot ulcers in their life time. Diabetic foot ulceration and i nfections are a major cause of hospitalization of diabetic patients. The direct and indirect costs of ulcer management and treatment exceed 10 billion dollars per year. In spite of this, approximately 1000 amputations are still performed on people with dia betes each week in the USA due to the lack of effective therapy for diabetic foot ulcers. Attempts to treat diabetic foot ulcers with growth factors have resulted in little success. Increasing evidence indicates that TGF-a is involved in the early and late phases of peripheral neuropathy and microvascular disease, both of which contribute to the development of diabetic foot ulcers. In diabetic patients, the plasma level of TGF-a is increased; TGF-a expression is also increased in diabetic wounds. TGF-a is a potent chemoattractant for inflammatory cells and inhibitor of endothelial and epithelial cell growth. It has been implicated in prolonged inflammation, defective angiogenesis and retarded wound re-epithelialization, as seen in diabetic foot ulcers. TGF-a appears to be an ideal therapeutic target for treating diabetic foot ulcers. However, no effective TGF-a antagonists have been developed. Recently, we developed TGF-a peptide antagonists (termed TGF-a peptantagonists) which are the only known TGF-a recept or antagonists and have been shown to accelerate normal wound healing in several animal burn/excision wound models. The efficacy of TGF-a peptantagonists in accelerating wound healing is limited by its poor solubility in aqueous solutions at neutral pH. Th e proposed research aims at developing novel TGF-a antagonists with excellent solubility, potent activity and high wound-penetration activity, based on the current chemical forms of TGF-a peptantagonists. The new forms of TGF-a peptantagonists developed in these studies should be excellent candidate drugs for treating diabetic foot ulcers. PUBLIC HEALTH RELEVANCE the goal of this project is to develop therapeutic agents for diabetic foot ulcers which currently lack effective treatments. The novel antagonist s developed in this project should be ideal drug candidates for treating diabetic foot ulcers in humans.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 998.03K | Year: 2010

DESCRIPTION (provided by applicant): Every year in the United States, gt1.25 million people suffer from burns, 6.5 million have chronic skin ulcers caused by pressure, venous stasis or diabetes mellitus and 0.25 million have keloids sufficiently severe to require surgery. Burn treatment costs 1.8 billion per year in the US. The treatment of persons with chronic skin ulcers costs 13 billion per year in the US. The annual cost of diabetic peripheral neuropathy and/or neuropathic foot ulcers in the U.S. is 0.8 billion for type I diabetics and 10.1 billion for type II diabetics. Limb-sparing surgical procedures are also widely used. In spite of these large costs for the care and the treatment of diabetic foot ulcers, each year 82,000 limb amputations are still performed on US patients with diabetic ulcers because current therapy is not very effective. These surgical treatments cost about 0.3 billion per year in the US. Currently, there is no agent which has been shown to be effective for treating cutaneous wounds. As these costs suggest, there is an urgent need for developing effective agents to accelerate wound healing and reduce scarring or tissue fibrosis in patients with burn injuries, blast injuries, chronic skin ulcers, keloids and other similar disorders. New products to treat these patients will drive the market. Accumulating evidence indicates that TGF-2, a cytokine, provides an ideal target for developing novel therapeutic agents for many types of wounds including chronic wounds. TGF-2 is produced at the wound site and is responsible for recruiting inflammatory cells and fibroblasts to the wound site, inhibiting epithelial cell growth (wound re-epithelialization) and stimulating extracellular matrix synthesis by fibroblasts (fibrosis) at the wound site. In prior studies, we developed a synthetic TGF-2 peptide antagonist (termed TGF-2 peptantagonist) which is the only known synthetic TGF-2 receptor antagonist. TGF-2 peptantagonist can enhance wound healing and reduce scarring in pig skin burn/excision and rabbit skin excision wound models. However, the efficacy of the synthetic TGF-2 peptantagonist is limited by its poor solubility in aqueous solution. This project aims at developing new chemical forms of our TGF-2 peptantagonist with excellent solubility, high tissue penetration ability and potent TGF-2 antagonist activity as drug candidates for treating wounds in humans. In Phase I studies, we have developed two new TGF-2 peptantagonists with rationally engineered properties exhibit high solubility in aqueous solution and are 10-times more potent than the prototype (unmodified) TGF-2 peptantagonist in inhibiting TGF-2 activity in vitro. One of these two new TGF-2 peptantagonists has been shown to potently prevent tissue injury, accelerate wound healing and reduce scarring in several animal injury models. These promising results have provided rationales for the proposed studies in the Phase II project. We hope the clinical availability of these two novel TGF-2 peptantagonists will be commercialized by large pharmaceutical companies, eventually directly benefiting individuals with various types of wounds including normal, impaired and chronic wounds. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop synthetic TGF-2 antagonists into wound healing agents for accelerating wound healing and reducing scarring. The clinical availability of these agents would benefit millions of patients who suffer from various types of wounds including normal, impaired and chronic wounds.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 199.47K | Year: 2007

DESCRIPTION (provided by applicant): Pulmonary fibrosis, a group of incurable lung diseases with high mortality rates, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins in lung parenchyma. Globally, five million people are affected by pulmonary fibrosis. In the U.S. alone, 200,000 suffer from this disease. Of these more than 40,000 die annually, equivalent to the number who die from breast cancer, and forty times more than those who die from cystic fibrosis. The effect of pulmonary fibrosis on quality of life is severe. Currently, there are no effective treatments for pulmonary fibrosis. Hence there is an urgent need to develop therapeutic agents that delay or reverse pulmonary fibrosis. Accumulating evidence indicates that transforming growth factor-beta (TGF-a) plays an important role in the pathogenesis of pulmonary fibrosis. Studies have shown that antagonizing TGF-a appears to ameliorate lung fibrosis. Therefore TGF-a antagonists may serve as important therapeutic agents for pulmonary fibrosis. We recently developed a class of synthetic TGF-a peptide antagonists (termed TGF-a peptantagonists) that antagonize TGF-a activity in cultured cells. Topical application of gel containing TGF-a peptantagonist promotes wound healing and attenuates fibrosis in standard animal skin injury models. However, the use of TGF-a peptantagonists for treating pulmonary fibrosis is limited by its poor solubility in aqueous solution at neutral pH. The goal of this proposal is to develop novel TGF-a peptantagonist derivatives with increased solubility, long plasma half-life, and potent antagonist activity. These agents should be effective for treating pulmonary fibrosis by inhalation and intravenous routes. Preliminary studies indicate that a high-molecular-weight TGF-a peptantagonist derivative we have recently developed that has excellent solubility and potent antagonist activity, effectively ameliorates bleomycin-induced lung fibrosis in mice. These results suggest that TGF-a antagonism may be a viable therapeutic strategy. In this proposal there are two specific aims: 1) to generate higher-molecular-weight derivatives of TGF-a peptantagonists with potent antagonist activity. The methodologies will include chemical synthesis, biochemical, cell biological and plasma clearance assays and 2) to determine the therapeutic effects of higher-molecular-weight derivatives of TGF-a peptantagonist on bleomycin-induced pulmonary fibrosis in mice. The methodologies will include biochemical, histological and semi-quantitative histopathological analyses. The new forms of TGF-a peptantagonist developed in these studies should be ideal drug candidates for treating pulmonary fibrosis in humans. The goal of this project is to develop therapeutic agents for pulmonary fibrosis which currently lacks effective treatments. The novel antagonists developed in this project should be ideal drug candidates for treating pulmonary fibrosis in humans.

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