Apolipoprotein E is a 34 kDa, 299 amino acid protein that folds into a helical horseshoe configuration which contains a distinct LDL receptor-binding domain, corresponding to amino acids 134 to 150 of the amino-terminus, as well as a major lipid-binding domain, corresponding to amino acids 244 to 272 of the carboxy-terminus. The amino-terminus of apolipoprotein E is comprised of a four amphipathic alpha-helices, with the LDL receptor-binding domain located in helix 4. Apolipoprotein E mimetic peptides, which correspond to the LDL receptor-binding domain, have been shown to bind LDL receptor family members and thereby suppress inflammation and neurotoxicity, as well as to mediate anti-viral effects. We have demonstrated that systemic administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130 149 of the full-length protein, can rescue the asthmatic phenotype of apoE knockout mice and attenuate the induction of house dust mite-induced asthma (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). We have also demonstrated that administration of an apoA-I mimetic peptide that was invented by Dr. Alan Remaley, attenuates the induction of house dust mite-induced asthma (Journal of Immunology 2011;186: 576-583). Ongoing projects are further defining the role of apolipoprotein E and apolipoprotein A-I mimetic peptides as a potential new therapeutic approach for asthma. The pre-clinical data generated from this project demonstrating the efficacy of aerosolized delivery to the lung will be used to support future clinical trials of this approach in patients with severe asthma.

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Project End
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Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
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Yao, Xianglan; Gordon, Elizabeth M; Barochia, Amisha V et al. (2016) The A's Have It: Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma. Chest 150:283-8
Dai, Cuilian; Yao, Xianglan; Vaisman, Boris et al. (2014) ATP-binding cassette transporter 1 attenuates ovalbumin-induced neutrophilic airway inflammation. Am J Respir Cell Mol Biol 51:626-36
Mishra, Amarjit; Yao, Xianglan; Levine, Stewart J (2013) From bedside to bench to clinic trials: identifying new treatments for severe asthma. Dis Model Mech 6:877-88
Dai, Cuilian; Yao, Xianglan; Keeran, Karen J et al. (2012) Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. Am J Respir Cell Mol Biol 47:186-95
Yao, Xianglan; Vitek, Michael P; Remaley, Alan T et al. (2012) Apolipoprotein mimetic peptides: a new approach for the treatment of asthma. Front Pharmacol 3:37
Yao, Xianglan; Dai, Cuilian; Fredriksson, Karin et al. (2011) 5A, an apolipoprotein A-I mimetic peptide, attenuates the induction of house dust mite-induced asthma. J Immunol 186:576-83
Yao, Xianglan; Remaley, Alan T; Levine, Stewart J (2011) New kids on the block: the emerging role of apolipoproteins in the pathogenesis and treatment of asthma. Chest 140:1048-54
Yao, Xianglan; Fredriksson, Karin; Yu, Zu-Xi et al. (2010) Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Am J Respir Crit Care Med :