Development of Apolipoprotein-based Therapeutics for Asthma

基于载脂蛋白的哮喘疗法的开发

• 批准号: 8149566
• 负责人: Stewart Levine
• 金额: $ 52.62万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149566
• 关键词: Apolipoproteins; Asthma; Development; Therapeutic; base

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). 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.

载脂蛋白E是一种34 kDa、299个氨基酸的蛋白质，折叠成螺旋马蹄形构型，其中包含一个独特的LDL受体结合结构域，对应于氨基末端的第134至150位氨基酸，以及一个主要的脂质结合结构域，对应于氨基酸244至272的羧基末端。 载脂蛋白E的氨基末端由四个两亲性α-螺旋组成，LDL受体结合结构域位于螺旋4中。 载脂蛋白E模拟肽，其对应于LDL受体结合结构域，已显示结合LDL受体家族成员，从而抑制炎症和神经毒性，以及介导抗病毒作用。 我们已经证明，全身给予载脂蛋白E模拟肽，对应于全长蛋白质的氨基酸130 - 149，可以挽救apoE基因敲除小鼠的哮喘表型，并减弱屋尘螨诱导的哮喘的诱导（载脂蛋白E负调节屋尘螨诱导的哮喘通过LDL受体介导的途径。 Yao X，Fredriksson K，Yu ZX，Xu X，Raghavachari N，Keiden KJ，Zywicke GJ，Kwak M，Amar MJ，Remaley AT，Levine SJ. Am J Respir Crit Care Med. 2010年7月9日。Epub before print）。 正在进行的项目正在进一步确定载脂蛋白E和载脂蛋白A-I模拟肽作为哮喘潜在新治疗方法的作用。 该项目产生的临床前数据证明了雾化输送至肺部的有效性，将用于支持该方法在重度哮喘患者中的未来临床试验。