Estradiol Regulation of Brain-Microvascular Inflammatory Responses in Sepsis

雌二醇对脓毒症脑微血管炎症反应的调节

基本信息

批准号：
9136873
负责人：
Candice Brown
金额：
$ 14.28万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136873
关键词：
Academia Acute Address Adherence Adhesions Affect Anti-Inflammatory Agents Anti-inflammatory Attenuated Blood Blood Vessels Brain Brain Injuries Cause of Death Cell Communication Cell Death Cell Survival Cells Cerebral Edema Cerebrovascular system Cerebrum Chronic Communities Confusion Coupled Delirium Development Plans Diffusion Magnetic Resonance Imaging Disease Edema Encephalitis Encephalopathies Endothelial Cells Endothelium Endotoxemia Estradiol Estrogens Female Functional disorder Future Genes Goals Histology Hour Imaging Device Imaging Techniques Immunomodulators Impairment Inflammation Inflammatory Inflammatory Response Intercellular adhesion molecule 1 Length Leukocyte Rolling Leukocytes Life Ligation Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Measures Metabolic Microcirculation Modeling Molecular Biology Morbidity - disease rate Motion Mus Neurologic Neurons Neurosciences Operative Surgical Procedures Ovarian Ovariectomy Pathway interactions Patients Phase Physiological Physiology Proteins Publications Puncture procedure Reaction Regulation Research Research Personnel Resolution Rodent Model Role Selectins Sepsis Staging T2 weighted imaging Teacher Professional Development Techniques Testing Therapeutic United States Vascular Cell Adhesion Molecule-1 Vascular System Work brain dysfunction brain metabolism career career development cerebral microvasculature cerebrovascular citizen science density design estrogenic forest immunocytochemistry improved in vivo innovation insight interdisciplinary approach intravital microscopy mRNA Expression medical schools microscopic imaging mouse model neuronal metabolism novel occludin programs shear stress skills sound therapy design tool vascular inflammation water diffusion

项目摘要

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.

描述（由申请人提供）：本 K01 提案的目标是为 Candice Brown 博士建立创新的研究策略和健全的职业发展计划，以成功过渡为神经科学领域的独立研究者。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。实验方法使用盲肠。脓毒症引起的脑功能障碍的结扎和穿刺模型，通常称为脓毒症相关脑病（SAE），导致约 70% 的脓毒症患者出现神经功能障碍，目标 1 的治疗选择将采用活体显微镜联合治疗。通过分子生物学确定 E2 是否可以减轻脑-微血管界面的血管炎症 Aim 2 将使用磁共振成像结合免疫细胞化学来确定 E2 是否可以减轻脑微血管界面处的血管炎症。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职业目标，其中包括：1）掌握手术技术和显微镜成像工具；2）获得能力。 MRI 及其作为研究急性脑功能障碍工具的能力； 3) 提高演示、出版和工艺技能，以及 4) 获得教师发展技能，成为一名富有成效的科学公民完成研究和职业目标将提供广泛的能力和一套有价值的工具，以建立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界的多样性。