Estradiol Regulation of Brain-Microvascular Inflammatory Responses in Sepsis

描述（由申请人提供）：本K01提案的目的是为Candice Brown博士建立一个创新的研究策略和健全的职业发展计划，以成功过渡到神经科学的独立研究者。该研究计划采用一种新颖的多学科方法来检验卵巢雌激素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诱导的脑功能障碍的假设。实验方法采用盲肠结扎和穿刺脓毒症引起的脑功能障碍模型，通常被称为脓毒症相关脑病（SAE）。SAE导致约70%的败血症患者神经功能受损，治疗选择有限。目的1将采用活体显微镜结合分子生物学来确定E2是否能减轻脑-微血管界面的血管炎症。Aim 2将使用磁共振成像联合免疫细胞化学来确定E2是否能减轻脓毒症早期和晚期的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的职业目标。这些包括：1)掌握手术技术和显微镜成像工具；2)掌握核磁共振成像技术及其作为研究急性脑功能障碍工具的能力；3)提高演讲、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有价值的工具，以建立一个富有成效的独立研究项目，并增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.