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

描述（由申请人提供）：在美国，子宫内生长受限（IUGR）占所有妊娠的5-10%，目前没有治疗方法。这些病例中的大多数是由于胎盘功能不全，研究表明，这些婴儿有高风险， 在成年期患上肥胖症、糖尿病和心血管疾病。长期目标是建立一个独立的实验室，研究胎盘功能和胎盘基因转移后的编程，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在生长受限的小鼠模型中开发用于胎盘胰岛素样生长因子1基因转移的载体，并获得对IGF-1的胎盘机制的新见解。我的中心假设是，IGF-1基因治疗后IGF-1过度表达诱导的胎盘营养转运增加构成了基因治疗纠正胎儿生长受限的一种机制。该假设是根据申请人和导师实验室的初步数据制定的。这一提议背后的基本原理是，它有望扩大IGF-1在体内胎盘中作用的知识，并产生胎盘基因转移的新技术，同时，它提供了将候选人建立为独立研究者的手段。为了检验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标：1）为了证明IGF-1的胎盘内基因转移纠正胎盘功能不全并恢复胎盘，IUGR小鼠模型的胎儿和出生后生长（将在指导阶段完成）和2）为了确定是否纠正胎儿生长受限后，IGF-1，1基因转移是由于胎盘营养转运增加（在独立期完成）。在第一个目标下，候选人将接受基因治疗技术的培训，并制定胎盘IGF-1基因转移的策略，之后将分析胎盘中IGF-1过度表达对胎盘生长和发育以及胎儿和产后生长的影响。在第二个目标下，体外和体内的功能和分子研究将确定胎盘营养转运在IGF-1介导的胎儿生长恢复中的参与，并提供对胎盘IGF-1机制的深入了解。使用IGF-1的位点特异性胎盘内基因转移是高度创新的，挑战了当前用于管理IUGR的范例，并且可以提供对IGF-1的胎盘机制的新见解。它还提供了一种实验手段来测试巴克的胎儿编程假设，并预防成人疾病，如肥胖，糖尿病，高血压和心血管疾病。这项研究意义重大，因为它有可能推动胎盘基因治疗策略机制的发展和理解，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的IUGR治疗方法。 公共卫生相关性：拟议的研究和培训与公共卫生有关，因为胎盘基因转移的发展和对胎盘中IGF-1功能的更多了解将导致胎盘功能不全，胎儿生长受限的潜在治疗，并降低患糖尿病等成人疾病的风险。因此，建议的研究是相关的NIH的使命的一部分，涉及到促进创新的研究策略和他们的应用，最终保护和改善健康的基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The proposed research and training is relevant to public health because the development of placental gene transfer and the increased understanding of IGF-1 function in the placenta would lead to a potential treatment for Placental Insufficiency, Fetal Growth Restriction and a reduced risk of developing adult diseases such as diabetes. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to fostering innovative research strategies and their applications as a basis for ultimately protectin and improving health.