Estradiol Regulation of Brain-Microvascular Inflammatory Responses in Sepsis

描述(申请人提供)：这份K01提案的目标是为坎迪斯·布朗博士建立一个创新的研究战略和完善的职业发展计划，以成功过渡到神经科学领域的独立研究员。该研究计划实施了一种新的、多学科的方法来测试卵巢雌激素17�-雌二醇(E2)通过改变脑-微血管界面的炎症机制来改变脓毒症引起的脑功能障碍的假设。实验方法采用盲肠结扎和穿刺术建立脓毒症引起的脑功能障碍模型，通常称为脓毒症相关性脑病(SAE)。SAE导致约70%的脓毒症患者出现神经功能障碍，治疗选择有限。目的1将使用活体显微镜和分子生物学相结合的方法来确定E2是否可以减轻脑-微血管界面的血管炎症。目的2将使用磁共振成像和免疫细胞化学相结合的方法来确定在脓毒症的早期和晚期，雌二醇是否可以减轻脑水肿和代谢功能障碍。职业发展计划有四个具体目标，旨在实现短期和长期职业目标。这些包括：1)掌握手术技术和显微成像工具；2)获得MRI方面的能力，并将其用作研究急性脑功能障碍的工具；3)改进演示、出版和工艺技能；4)获得教师发展技能，成为学术界富有成效的科学公民。研究和职业目标的完成将提供广泛的能力和一套宝贵的工具，以建立一个富有成效的独立研究计划，并加强维克森林医学院神经科学社区的多样性。

DESCRIPTION (provided by applicant): The objective of this K01 proposal is to establish an innovative research strategy and sound career development plan for Dr. Candice Brown to successfully transition to an independent investigator in neuroscience. The research plan implements a novel, multidisciplinary approach to test the hypothesis that the ovarian estrogen, 17�-estradiol (E2), modifies sepsis-induced brain dysfunction by altering the inflammatory mechanisms at the brain-micro vascular interface. The experimental approach uses a cecal ligation and puncture model of sepsis-induced brain dysfunction, commonly referred to sepsis-associated encephalopathy (SAE). SAE results in neurological impairment in ~70% of sepsis patients, and therapeutic options for treatment are limited. Aim 1 will employ intravital microscopy combined with molecular biology to determine whether E2 attenuates vascular inflammation at the brain-micro vascular interface. Aim 2 will use magnetic resonance imaging combined with immunocytochemistry to determine whether E2 attenuates cerebral edema and metabolic dysfunction in the early and late stages of sepsis. The career development plan has four specific aims designed to achieve short and long term career goals. These include: 1) Mastering surgical techniques and microscopy imaging tools; 2) Acquiring competency in MRI and its capabilities to use as tool to study acute brain dysfunction; 3) Improving presentation, publication, and craftsmanship skills, and 4) Gaining faculty development skills to become a productive science-citizen in academia. Completion of Research and Career Aims will provide broad competencies and a valuable set of tools to establish a productive independent research program and enhance the diversity of the neuroscience community at Wake Forest School of Medicine.