Insulin-like Growth Factor 1 Gene Therapy; Correction of Placental Insufficiency

项目摘要 子宫内生长受限（IUGR）使美国所有妊娠的5-10%复杂化，目前 没有治疗。这些病例中的大多数是由于胎盘功能不全，研究表明， 婴儿在成年后患上肥胖症，糖尿病和心血管疾病的风险很高。长期 目标是建立一个研究胎盘功能和程序的独立实验室 在胎盘基因转移后，以建立胎儿生长受限的潜在治疗策略。 本申请的总体目标是开发胎盘胰岛素样生长因子1基因的载体 在生长受限的小鼠模型中转移，并对IGF-1的胎盘机制有了新的认识。 我的中心假设是IGF-1的过度表达引起胎盘营养物质转运的增加， 随后的IGF-1基因治疗构成了一种负责纠正胎儿生长的机制 基因治疗的限制。这一假设是根据1996年产生的初步数据提出的。 申请人和导师实验室。这一建议背后的理由是，预计将扩大 了解IGF-1在体内胎盘中的作用并产生胎盘基因转移的新技术， 与此同时，它提供了使候选人成为独立研究者的手段。测试 中心假设，并实现本申请的目标，候选人打算追求 以下具体目的：1）证明胎盘内IGF-1基因转移可纠正胎盘 在IUGR的小鼠模型中的不足和恢复胎盘、胎儿和出生后生长（待完成 在指导阶段）和2）为了确定是否纠正胎儿生长受限后IGF-1 基因转移是由于胎盘营养物质转运增加（在独立的 阶段）。根据第一个目标，候选人将接受基因治疗技术的培训， 胎盘IGF-1基因转移的策略，在此之后，IGF-1在胎盘中过度表达的影响 对胎盘生长和发育以及胎儿和产后生长的影响。第二个目标 体外和体内的功能和分子研究将确定胎盘营养转运的参与， 在IGF-1介导的胎儿生长恢复中的作用，并提供了对胎盘IGF-1机制的深入了解。网站的使用- IGF-1的特异性胎盘内基因转移是高度创新的，挑战了目前的范式， 管理IUGR，并可能提供新的见解IGF-1的胎盘机制。它还提供 一种实验手段来测试巴克的胎儿编程假设，并防止成人疾病，如 肥胖、糖尿病、高血压和心血管疾病。这项研究意义重大，因为它 有可能推动该领域的发展和理解的机制， 胎盘基因治疗策略，并进一步了解IGF-1在胎盘中的功能。最终 这些知识有可能导致开发出第一种有效治疗IUGR的方法。

Project Summary Intra-Uterine Growth Restriction (IUGR) complicates 5-10% of all pregnancies in the U.S.A and currently has no treatment. The majority of these cases are due to placental insufficiency and studies indicate that these babies are at high risk of developing obesity, diabetes and cardiovascular disease in adulthood. The long-term goal is to establish an independent laboratory with research interests in placental function and programming following placental gene transfer in order to establish potential treatment strategies for fetal growth restriction. The overall objective of this application is to develop vectors for placental Insulin-like Growth Factor 1 gene transfer in a mouse model of growth restriction and gain new insight into the placental mechanisms of IGF-1. My central hypothesis is that increased placental nutrient transport induced by over-expression of IGF-1 following IGF-1 gene therapy constitutes one mechanism responsible for the correction of fetal growth restriction by gene therapy. The hypothesis has been formulated on the basis of preliminary data produced in the applicants and mentors laboratory. The rationale behind this proposal is that it is expected to broaden the knowledge of IGF-1 actions in the placenta in vivo and yield new technologies for placental gene transfer while, at the same time, it provides the means of establishing the Candidate as an independent researcher. To test the central hypothesis and accomplish the objective of this application the candidate intends to pursue the following specific aims: 1) To demonstrate that intraplacental gene transfer of IGF-1 corrects placental insufficiency and restores placental, fetal and postnatal growth in a mouse model of IUGR (to be accomplished during the mentored phase) and 2) To determine if the correction of fetal growth restriction following IGF-1 gene transfer is due to increased placental nutrient transport (to be accomplished during the independent phase). Under the first aim the candidate will receive training in gene therapy techniques and develop strategies for placental IGF-1 gene transfer, after which the effect of over-expression of IGF-1 in the placenta on placental growth and development and fetal and post-natal growth will be analyzed. Under the second aim functional and molecular studies in vitro and in vivo will identify the involvement of placental nutrient transport in IGF-1 mediated fetal growth recovery and provide insight into placental IGF-1 mechanisms. The use of site- specific intraplacental gene transfer of IGF-1 is highly innovative, challenging current paradigms for the management of IUGR and may provide new insights into the placental mechanisms of IGF-1. It also provides an experimental means to test Barker's fetal programming hypothesis and to prevent adult diseases such as obesity, diabetes, hypertension and cardiovascular disease. The proposed research is significant because it has the potential to move the field forward in the development of and understanding of the mechanisms of placental gene therapy strategies and furthering our knowledge of IGF-1 function in the placenta. Ultimately such knowledge has the potential to lead to the development of the first effective treatment for IUGR.