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：
8425399
负责人：
Candice Brown
金额：
$ 14.28万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
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 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8425399
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 Cerebrum Chronic Communities Confusion Coupled Delirium Development Development Plans Diffusion Magnetic Resonance Imaging Disease Edema Encephalitis Encephalopathies Endothelial Cells Endothelium Endotoxemia Estradiol Estrogens Faculty Female Functional disorder Future Genes Goals Histology Hour Image 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 Metabolism Microcirculation Microscopy 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 Science Selectins Sepsis Staging Techniques Testing Therapeutic United States Vascular Cell Adhesion Molecule-1 Vascular System Weight Work brain metabolism career career development cerebrovascular density design forest immunocytochemistry improved in vivo innovation insight interdisciplinary approach intravital microscopy mRNA Expression medical schools mouse model 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. PUBLIC HEALTH RELEVANCE: Brain damage from inflammation occurs in approximately 70% of patients with sepsis, the 10th leading cause of death in the United States. Ovarian estrogens exert powerful anti-inflammatory activity on the brain's vascular system and determining whether estrogen decreases brain inflammation in sepsis can guide future therapies designed to protect brain function and diminish loss of life.

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。检验卵巢雌激素的假设，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该实验方法使用脓毒症引起的脑功能障碍的盲肠结扎和穿刺模型，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结合分子生物学来确定是否存在。 E2减轻脑-微血管界面的血管炎症。目标2将使用磁共振成像结合免疫细胞化学来确定E2是否减轻脓毒症早期和晚期的脑水肿和代谢功能障碍。该职业发展计划设计了四个具体目标。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 MRI 的能力及其作为研究工具的能力。急性脑功能障碍；3) 提高演讲、出版和工艺技能，以及 4) 获得教师发展技能，成为学术界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。富有成效的独立研究计划，并增强维克森林医学院神经科学界的多样性。公共健康相关性：大约 70% 的脓毒症患者会出现炎症引起的脑损伤，脓毒症是美国第十大死因，卵巢雌激素对大脑血管系统具有强大的抗炎活性，并决定雌激素是否可以减少脑部炎症。脓毒症可以指导未来旨在保护大脑功能和减少生命损失的治疗方法。