Administrative Supplements to Existing NIH Grants and Cooperative Agreements

对现有 NIH 拨款和合作协议的行政补充

基本信息

批准号：
9929915
负责人：
CHRIS B SCHAFFER
金额：
$ 32.97万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9929915
关键词：
APP-PS1 Adhesions Administrative Supplement Adult Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Antibodies Automobile Driving Behavior Behavioral Blocking Antibodies Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Brain Brain Diseases Cell Surface Proteins Cell Wall Cell physiology Cells Cerebrovascular Circulation Complex Data Development Disease Drug Targeting Endothelial Cells Ensure Environment Episodic memory Exposure to Female Fluorescence Microscopy Funding Gene Expression Genes Goals Grant Histologic Hour House mice Housing Human Immune Immune response Immune system Immunocompromised Host Immunology Incidence Inflammation Inflammatory Inflammatory Response Knowledge Laboratories Laboratory mice Lead Leukocytes Link Measurement Measures Medical Memory Memory impairment Mental Depression Microbiology Microglia Molecular Molecular Target Mus NADPH Oxidase Nature Neurobehavioral Manifestations Neurosciences Oxidases Pathology Pathway interactions Patients Performance Permeability Phenotype Proteins Senile Plaques Sensory Series Signal Transduction Speed Sterility T-Lymphocyte Time Tissues U-Series Cooperative Agreements United States National Institutes of Health Wild Type Mouse Work adaptive immune response brain endothelial cell cell behavior cerebral capillary cerebral microvasculature cognitive function cohort experimental study gut microbiota improved in vivo microbial motor disorder mouse model multiphoton imaging neutrophil normal microbiota novel novel therapeutics pregnant recruit side effect superoxide-generating NADPH oxidase transcriptome sequencing two-photon vascular inflammation

项目摘要

Project Summary: Substantial brain blood flow reductions are observed in Alzheimer’s disease (AD) patients and likely contribute to the cognitive symptoms of the disease. Recent work using in vivo multiphoton imaging has shown that neutrophil adhesion in brain capillaries is a cellular mechanism that causes reduced brain blood flow in AD mouse models, and has further shown that cognitive function is rapidly improved when neutrophil adhesion is blocked to increase brain blood flow. These results suggest that improved understanding of the nature and molecular causes of the vascular inflammation in the AD brain could suggest novel therapeutic strategies, complementary to anti-Amyloid and other treatment approaches currently in development, that aim to improve brain blood flow and potentially reduce cognitive symptoms of AD. In this request for supplemental funding, the aim is to pursue two important extensions of the existing grant. The first goal is to assess the impact of the clean environment the mouse models live in. The effect that underlies the decreased brain blood flow in AD mice is subtle — about 2% of brain capillaries are not flowing due to an adhered neutrophil. Several studies have shown that immune and inflammatory cell behavior in laboratory mice is altered when those mice are exposed to the flora of wild mice. AD and wild-type mice will be exposed to the flora of mice from pet shops, with controls kept in standard laboratory housing conditions. The incidence and cause of capillary stalling and the impact of capillary stalls on brain blood flow will be compared between these groups to determine if altered inflammatory cell phenotypes due to the clean environment of laboratory mice influences the capillary stalling phenomena that underlies brain blood flow deficits in AD mice. This work extends Aim 1 of the original proposal, which seeks to characterize the incidence and cause of non-flowing capillaries in AD mice. The second goal relates to increasing our understanding of the vascular inflammation that leads to increased neutrophil adhesion in capillaries in the AD mice. Recent work has shown that inhibition of NOX2-containing NAPDH oxidase, a reactive oxygen producing enzyme, decreases the incidence of capillary stalling in AD mice. Here, the proposal is to extract brain endothelial cells from AD and wild-type mice with and without inhibition of NAPDH oxidase, and use RNA sequencing to determine differences in gene expression between these four groups. Newly developed approaches that do not overly activate the endothelial cells during extraction and processing will be utilized. Such work to clarify the details of the inflammatory response is critically important for identifying a potential drug target to block this effect and improve brain blood flow in patients. Long term, systemic inhibition of neutrophil adhesion could have hard to manage side effects, and this gene expression data will help to identify a place to intervene that is more brain endothelia and AD specific. This work extends Aim 2 of the original proposal, which aims to identify the molecular signaling that leads to increased capillary stalling in AD mice.

项目摘要：在阿尔茨海默氏病（AD）患者中观察到大量脑血流量减少并可能导致该疾病的认知症状。最近使用体内多光子成像的工作已经表明，脑毛细血管中的嗜中性粒细胞粘合剂是导致脑部减少的细胞机制 AD小鼠模型中的血流，并进一步表明，当认知功能迅速提高中性粒细胞粘附被阻断以增加脑血流。这些结果表明改善了了解广告大脑中血管炎症的性质和分子原因可能表明新型的热策略，抗淀粉样蛋白和其他治疗方法目前发展，旨在改善脑血流并有可能减少AD的认知症状。在这个要求补充资金的要求，目的是追求现有赠款的两个重要扩展。第一个目标是评估鼠标模型所生活的清洁环境的影响。 AD小鼠的脑血流改善很微妙 - 大约2％的脑毛细血管不流动粘附的中性粒细胞。几项研究表明，实验室的免疫和炎症细胞行为当这些小鼠暴露于野生小鼠的菌群时，小鼠会改变。 AD和野生型小鼠将暴露到宠物店的小鼠植物群，并在标准实验室住房条件下保存了控件。事件将比较毛细管失速的原因以及毛细管摊位对脑血流的影响这些组以确定由于实验室清洁环境而导致的炎症细胞表型是否改变小鼠会影响脑血流定义的毛细管失速现象。这项工作扩展了原始提案的目标1，该提议旨在表征事件和原因不流动的原因 AD小鼠的毛细血管。第二个目标与我们对血管炎症的理解有关这导致AD小鼠毛细血管中的中性粒细胞广告增加。最近的工作表明抑制含有NOX2的NAPDH氧化物，一种产生的活性氧，可降低 AD小鼠毛细管失速的发生率。在这里，建议是从AD中提取脑内皮细胞，野生型小鼠有和不抑制NAPDH氧化物，并使用RNA测序确定这四组之间的基因表达差异。新开发的方法不会过分将利用在提取和加工过程中激活内皮细胞。这样的工作以澄清细节炎症反应的重要性对于确定潜在的药物靶标至关重要并改善患者的脑血流。长期，系统性抑制中性粒细胞粘附可能具有难以管理副作用，此基因表达数据将有助于确定干预的地方更多的大脑内皮和广告特定。这项工作扩展了原始提案的目标2，旨在确定导致AD小鼠毛细管停滞增加的分子信号传导。