An Autophagy^lnducing Peptide as a Novel Therapeutic for Intracellular NIAID Cla

自噬诱导肽作为细胞内 NIAID Cla 的新疗法

• 批准号: 8567979
• 负责人: BETH C LEVINE
• 金额: $ 45.88万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567979
• 关键词: Advanced Development; Autophagocytosis; Bacteria; Biological; Biological Assay; Biological Products; Categories; Chikungunya virus; Development; Disease; Dose; Drug Kinetics; Growth; In Vitro; Infection; Investigation; Lysosomes; Measures; Mus; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Natural Immunity; Organ; Pathogenesis; Peptides; Pharmacodynamics; Phase; Property; Rickettsia; Safety; Sampling; Surveys; Toxic effect; Virus; West Nile virus; Work; antimicrobial; biodefense; combat; immunogenic; immunogenicity; in vivo; microbial; mouse model; novel; novel therapeutic intervention; novel therapeutics; pathogen; pre-clinical; preclinical evaluation; small molecule; tissue culture

The autophagic delivery of intracellular pathogens to the lysosome (where they are destroyed) is emerging as a central mechanism of innate immunity; accordingly, the augmentation of host autophagy represents a potentially powerful new therapeutic approach to combat intracellular pathogens1-3. In our original project, we pursued four specific aims to develop an autophagy-inducing peptide that may be useful as a novel therapeutic in the treatment of diverse intracellular NIAID Class A, B, and C Priority pathogens. These aims included: 1. To confirm that the Tat-Beclin 1 peptide is a specific inducer of autophagy in vitro and in vivo. 2. To evaluate the mechanism by which the Tat-Beclin 1 induces autophagy. 3. To evaluate the effects of the Tat-Beclin 1 peptide on the in vitro growth of selected NIAID Category A, B, and C Priority Pathogens. 4. To evaluate the effects of the Tat-Beclin 1 peptide on microbial pathogenesis in mouse models of infection with selected NIAID Category A, B, and C Priority Pathogens. Thus far, we have completed the first aim and made significant progress towards completing Aims 2-4. To accelerate the development of a novel broad-spectrum antimicrobial biological product, the Tat-Beclin 1 autophagy-inducing peptide, we propose to work further on Aims 2-4 in parallel with investigations to determine the optimal dosing, immunogenicity, and preliminary safety profile of the peptide. These studies will help advance the development of a biologically active peptide (or small molecule compound that mimics its action) for the treatment of NIAID priority intracellular pathogens.

细胞内病原体的自噬传递到溶酶体（在那里它们被破坏）正在出现， 先天免疫的中心机制;因此，宿主自噬的增强代表了 潜在的强大的新的治疗方法，以打击细胞内病原体1 -3。在我们最初的项目中，我们 追求四个具体的目标，开发一种自噬诱导肽，可能是有用的新的治疗方法， 治疗多种细胞内NIAID A、B和C类优先病原体。这些目标包括： 1.证实Tat-Beclin 1肽是体外和体内自噬的特异性诱导剂。 2.评估Tat-Beclin 1诱导自噬的机制。 3.为了评价Tat-Beclin 1肽对所选NIAID A类的体外生长的影响， B和C优先病原体。 4.为了评估Tat-Beclin 1肽对小鼠模型中微生物致病性的影响， 感染选定的NIAID A、B和C类优先病原体。 到目前为止，我们已经完成了第一个目标，并在实现目标2-4方面取得了重大进展。到 加快新型广谱抗菌生物制品Tat-Beclin 1的开发 自噬诱导肽，我们建议进一步研究目标2-4与调查平行，以确定 肽的最佳剂量、免疫原性和初步安全性特征。这些研究将有助于 推进生物活性肽（或模拟其作用的小分子化合物）的开发 用于治疗NIAID优先细胞内病原体。