Novel role for placental endothelial mitochondria in preeclampsia

项目摘要 这个K08应用程序是为詹妮弗麦金托什博士，在医学的产妇胎儿医学助理教授 威斯康星州的一位科学家正在建立她的研究利基，作为一名研究线粒体的医生科学家 人类胎盘功能障碍是先兆子痫的一种机制。这个奖能让麦金托什博士 开发研究项目和合作关系所需的时间和资源。她有 建立了指导和咨询团队，其中包括大卫Gutterman博士，人类血管专家， 微循环反应性，哈特穆特·韦勒博士，细胞和分子机制相关的专家， 凝血和胎盘发育，艾伦考利博士，国际公认的综合生理学家 他在高血压方面的研究，以及血管生物学专家Nicole Lohr博士， 胎盘脉管系统麦金托什博士还与外部机构的经验交织在一起， 尖端的胎盘技术以及线粒体下一代测序，以确保她实现 他的职业发展目标和研究目标。先兆子痫仍然是一个世界性的问题， 每年有100万孕妇受到影响，50多万围产期死亡。先兆子痫是一种 上升，和潜在的病理生理机制先兆子痫仍然知之甚少。血管 胎盘和母体血管系统内的功能障碍和内皮损伤有助于高血压 妊娠期疾病。线粒体损伤和内皮细胞凋亡之间可能存在一种新的关系。 功能障碍和随后的先兆子痫的发展。总的假设是， 胎盘灌注，缺血导致活性氧增加，炎症和 线粒体DNA损伤（mtDNA），通过TLR，促进促氧化和炎症环境， 胎盘血管系统导致内皮功能障碍，最终导致先兆子痫。探讨 根据这一假设，麦金托什博士将1）确定胎盘缺氧是否会诱导mtDNA损伤， 胎盘样本在缺氧环境中，2）测试是否增加了血管中的mtDNA损伤， 先兆子痫胎盘通过Toll样受体导致内皮依赖性扩张受损。 将使用视频显微镜和导丝肌造影术检测血管扩张能力、血流介导扩张（FMD）， 以及先兆子痫患者胎盘血管中线粒体DNA升高导致的FMD改变， 是否可以通过抑制Toll样受体来逆转。这些研究可能提供一种机制，可以 最终成为治疗干预的目标。通过麦金托什博士提出的职业发展计划， 她将成为人类胎盘微循环和线粒体血管生物学方面的专家 功能障碍这些技能将使McIntosh博士能够开发她的R01应用程序，并最终成为领导者 在外地

Project Summary This K08 application is for Dr. Jennifer McIntosh, an assistant professor of Maternal Fetal Medicine at the Medical College of Wisconsin who is building her research niche as a physician-scientist studying mitochondrial dysfunction within the human placenta as a mechanism for preeclampsia. This award would afford Dr. McIntosh the time and resources that she needs to develop the research project and collaborative relationships. She has established mentoring and consultative teams that include Dr. David Gutterman, an expert in human vascular reactivity in the microcirculation, Dr. Hartmut Weiler, an expert in cellular and molecular mechanisms relating to coagulation and placental development, Dr. Allen Cowley, an integrative physiologist internationally recognized for his research in hypertension, and Dr. Nicole Lohr, an expert in vascular biology and experience with the placental vasculature. Dr. McIntosh has also woven in experience with outside institutions to gain expertise in cutting edge placental techniques as well as mitochondrial next generation sequencing to ensure she achieves her career development goals and research aims. Preeclampsia remains a worldwide problem with over 10 million pregnant women impacted and over half a million perinatal lives lost annually. Preeclampsia is on the rise, and the underlying pathophysiological mechanism of preeclampsia remains poorly understood. Vascular dysfunction and endothelial damage within the placenta and maternal vasculature contribute to hypertensive disorders of pregnancy. A novel relationship may exist between mitochondrial damage and endothelial dysfunction and subsequent development of preeclampsia. The overall hypothesis is that with decreased placental perfusion, ischemia results in increased reactive oxygen species, inflammation, and release of mitochondrial DNA damage (mtDNA) that, via TLRs, promote a pro-oxidative and inflammatory environment in the placental vasculature that result in endothelial dysfunction that culminates in preeclampsia. To investigate this hypothesis, Dr. McIntosh will 1) determine whether placental hypoxia induces mtDNA damage using placental samples within a hypoxic environment and 2) test whether heightened mtDNA damage in vessels from preeclamptic placentas is responsible for impaired endothelial dependent dilation via toll-like receptors. Videomicroscopy and wire myography will be used to test vasodilator capacity, flow mediated dilation (FMD), and altered FMD as a result of heightened mtDNA in vessels from placentas in those with preeclampsia and whether that could be reversed by inhibiting toll-like receptors. These studies may provide a mechanism that can ultimately be targeted for therapeutic intervention. Through Dr. McIntosh’s proposed career development plan, she will become an expert in the vascular biology of the human placental microcirculation and mitochondrial dysfunction. These skills will position Dr. McIntosh to develop her R01 application and ultimately become a leader in the field.