Minority Predoctoral Fellowship Program

少数族裔博士前奖学金计划

• 批准号: 6686046
• 负责人: ERICA LYNN BRADSHAW PIERCE
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6686046
• 关键词: angiogenesis; athymic mouse; biological models; biotechnology; breast neoplasms; cell line; deoxyribopolynucleotide; gene delivery system; gene therapy; growth factor receptors; laboratory mouse; ligands; lipids; liposomes; model design /development; neoplasm /cancer blood supply; neoplasm /cancer pharmacology; neoplasm /cancer therapy; pharmacokinetics; plasmids; predoctoral investigator; transfection; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Gene therapy provides a viable treatment alternative for an array of diseases and disorders. Due to the well-known toxicity and immunogenicity of viral vectors, the development of synthetic delivery systems is gaining attention. Unfortunately, very little attention has been paid to the pharmacokinetics and development of predictive models. The overall goal of this proposal is to develop an understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of liposome mediated delivery of plasmid DNA, and to utilize this information to develop physiologically-based pharmacokinetic (PBPK) models. Initially, normal healthy mice will be used to optimize a liposome delivery vehicle and develop and validate a PBPK model. The incorporation of a ligand to the liposome:DNA complex should increase transfection of the gene and minimize delivery and expression in untargeted cells/tissues. This will be tested both in vitro and in vivo. Since synthetic DNA has shown to target expression in endothelial cells, we intend to incorporate a VEGF receptor ligand in hopes to further enhance delivery to vascular endothelial cells, and later incorporate a gene to prohibit angiogenesis. Tumor xenograft models will be used to investigate the PK and PD of vascular endothelium targeted gene therapeutics, and validated PBPK models will be developed.

描述（由申请人提供）：基因疗法为一系列疾病和病症提供了可行的治疗替代方案。由于病毒载体众所周知的毒性和免疫原性，合成递送系统的开发正在引起人们的关注。不幸的是，人们很少关注药代动力学和预测模型的开发。该提案的总体目标是加深对脂质体介导的质粒 DNA 递送的药代动力学 (PK) 和药效学 (PD) 的了解，并利用这些信息开发基于生理学的药代动力学 (PBPK) 模型。最初，将使用正常健康小鼠来优化脂质体递送载体并开发和验证 PBPK 模型。将配体掺入脂质体：DNA复合物应增加基因的转染并最大限度地减少非靶向细胞/组织中的递送和表达。这将在体外和体内进行测试。由于合成 DNA 已显示在内皮细胞中靶向表达，因此我们打算掺入 VEGF 受体配体，希望进一步增强向血管内皮细胞的递送，随后掺入基因以抑制血管生成。肿瘤异种移植模型将用于研究血管内皮靶向基因治疗的PK和PD，并开发经过验证的PBPK模型。