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

• 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
• 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

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K 01提案的目的是为Candice Brown博士建立一个创新的研究策略和合理的职业发展计划，以成功过渡到神经科学的独立研究者。该研究计划实施了一种新的多学科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诱导的脑功能障碍的假设。实验方法使用盲肠结扎和穿孔脓毒症诱导的脑功能障碍模型，通常称为脓毒症相关脑病（SAE）。SAE在约70%的脓毒症患者中导致神经功能损害，治疗选择有限。目的1将采用活体显微镜结合分子生物学，以确定是否E2减弱血管炎症在脑微血管接口。目的2：利用磁共振成像结合免疫细胞化学技术，探讨E2是否能减轻脓毒症早期和晚期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。这些措施包括：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急性脑功能障碍的工具的能力; 3）提高演讲，出版和工艺技能，以及4）获得教师发展技能，成为学术界的生产科学公民。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计划，并提高神经科学界的多样性在维克森林医学院。 公共卫生相关性：炎症引起的脑损伤发生在约70%的脓毒症患者中，脓毒症是美国第十大死亡原因。卵巢雌激素对脑血管系统具有强大的抗炎活性，确定雌激素是否能减少脓毒症中的脑炎症，可以指导未来旨在保护脑功能和减少生命损失的治疗方法。