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（由申请人证明）：卫冕症是主要因素的妊娠高血压障碍，以及在美国的所有怀孕中占8％，并可能导致孕妇癫痫发作的癫痫发作，这是造成的。和死亡。开发一种能够在母体中稳定新型治疗剂的药物，同时保护他们进入胎儿循环。这些途径。母体循环在阻止胎盘循环的同时，该提案的目的是1）评估药代动力学的目标，胎儿排除药物的过热f，2）评估体外机制和在ELP-VEGF Torapeutic在大鼠前启示性模型中的体内功效，3）评估ELP融合的体外机制和体内功效 NF-κB抑制性治疗模型和4）评估与测试剂的后代异常动机中高血压的发展。