A Novel Protein Delivery System for Therapy of Preeclampsia

用于治疗先兆子痫的新型蛋白质递送系统

基本信息

批准号：
8989144
负责人：
Gene Leflore Bidwell
金额：
$ 37.38万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8989144
关键词：
Affect Amino Acid Motifs Amino Acids Angiogenic Proteins Anti-Inflammatory Agents Anti-inflammatory Blood Circulation Brain Hypoxia-Ischemia Cardiovascular Physiology Cardiovascular system Cessation of life Characteristics Chimera organism Chronic Data Development Disease Drug Carriers Drug Delivery Systems Drug Kinetics Elastin Endothelial Cells Environment Escherichia coli Exclusion Failure Fetal Tissues Fetus Functional disorder Goals Health Hypertension In Vitro Infant Inflammatory Inflammatory Response Ischemia Lead Left Mediating Modeling Molecular Molecular Weight Morbidity - disease rate Mothers NF-kappa B Nuclear Import Nuclear Translocation Pathway interactions Peptides Perinatal mortality demographics Phase Physiological Placenta Plasma Polymers Pre-Eclampsia Pregnancy Premature Birth Proline Proteins Proteinuria Rattus Seizures Signal Transduction System TNF gene Testing Therapeutic Therapeutic Agents Tissues Treatment Efficacy Vascular Endothelial Growth Factors base cytokine effective intervention fetal immunogenicity in vivo inhibitor/antagonist macromolecule meetings mortality novel novel therapeutics offspring peptide drug perinatal morbidity polypeptide pregnancy disorder prevent response small molecule therapeutics targeted agent targeted treatment therapeutic protein therapeutic target vector

项目摘要

DESCRIPTION (provided by applicant): Preeclampsia is a common hypertensive disorder of pregnancy and is one of the leading causes of maternal, fetal, and perinatal morbidity and mortality. Affecting ~8% of all pregnancies in the US, preeclampsia displays characteristic hypertension, proteinuria, and altered cardiovascular function and, if left unchecked, can lead to maternal seizures and death. There is currently no effective intervention for preeclampsia short of induced delivery of the fetus, which is why it is also a leading cause of premature birth. Improvements in preeclampsia management have been largely stifled due to deleterious effects of various proposed small- molecule therapeutics on the developing fetus. The objective of the proposed studies is to develop a drug delivery system capable of stabilizing novel therapeutic agents in the maternal circulation while protecting them from entering the fetal circulation. The onset and progression of preeclampsia is driven by two major pathways, secretion of the VEGF antagonist sFlt-1 and induction of a highly inflammatory environment in the mother. We have developed two novel agents targeting each of these pathways, a supplementary VEGF therapy to counteract the increased sFlt-1 levels and an NF-kB inhibitory peptide therapy to block the inflammatory response. These therapeutics are attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes them in the maternal circulation while preventing them from crossing the placenta into the fetal circulation. The aims of this proposal are to 1) assess the pharmacokinetics, bio distribution, placental targeting, and fetal exclusion of several iterations f this drug carrier, 2) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-VEGF therapeutic in a rat preeclampsia model, 3) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-fused NF-κB inhibitory therapeutic in a rat preeclampsia model, and 4) assess the development of hypertension in the offspring of preeclamptic mothers treated with these test agents.

描述（由适用提供）：Precamia是一种常见的妊娠高血压障碍，是孕产妇，胎儿和围产期发病率和死亡率的主要原因之一。在美国影响约8％的美国，Precamia表现出特征性的高血压，蛋白尿和心血管功能改变，如果不受检查，则可能导致孕妇的癫痫发作和死亡。目前尚无有效的干预措施，因为胎儿的诱发递送也没有诱发的效果，这就是为什么它也是早产的主要原因。由于拟议的小分子疗法对发育中的胎儿的有害影响，前峰管理的改善在很大程度上被卡住了。拟议的研究的目的是开发一种能够稳定母体循环中新型治疗剂的药物输送系统，同时保护它们免于进入胎儿循环。前峰的发作和进展是由两种主要途径的驱动，即VEGF拮抗剂SFLT-1的分泌以及母亲高度炎症环境的诱导。我们已经开发了两种针对这些途径的新型药物，一种补充VEGF疗法，以抵消SFLT-1水平升高和NF-KB抑制性肽治疗，以阻止炎症反应。这些治疗剂附着在称为弹性蛋白样多肽（ELP）的药物递送载体上，该药物在母体循环中稳定它们，同时阻止它们将plopeta越过胎儿循环。该提案的目的是1）评估该药物载体的药代动力学，生物分布，占地靶向和胎儿排除几个迭代，2）评估ELP-VEGF治疗的体外机制和体内的体内效率，在大鼠preclampsia模型中，评估体外机制，3）评估体内的效率，3）评估体内的效率和VIV效率。大鼠前青期模型中的NF-κB抑制性疗法，以及4）评估用这些测试剂治疗的先兆母亲的后代中高血压的发展。