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：在阿尔茨海默病 (AD) 患者中观察到脑血流量大幅减少最近使用体内多光子成像的研究可能有助于该疾病的认知症状。研究表明，中性粒细胞在脑毛细血管中的粘附是导致脑细胞减少的一种细胞机制。 AD 小鼠模型中的血流，并进一步表明，当这些结果表明中性粒细胞粘附被阻断以增加脑血流量。了解 AD 大脑中血管炎症的性质和分子原因可能会提示新的治疗策略，补充抗淀粉样蛋白和目前的其他治疗方法旨在改善大脑血流量并可能减少 AD 的认知症状。请求补充资金，目的是对现有赠款进行两次重要的延期。第一个目标是评估小鼠模型居住的清洁环境的影响。其背后的影响 AD 小鼠的脑血流是微妙的——大约 2% 的脑毛细血管由于以下原因不流动一些研究表明，实验室中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，小鼠的基因就会发生改变，野生型小鼠也会受到影响。来自宠物店的小鼠菌群，对照保存在标准实验室饲养条件下。并将比较毛细血管失速的原因以及毛细血管失速对脑血流的影响这些小组确定炎症细胞表型是否归因于实验室的清洁环境小鼠影响 AD 小鼠脑血流缺陷的毛细血管停滞现象。扩展了最初提案的目标 1，该目标旨在描述不流动的发生率和原因第二个目标涉及增加我们对血管炎症的了解。最近的研究表明，这会导致 AD 小鼠毛细血管中的中性粒细胞粘附增加。抑制含有 NOX2 的 NAPDH 氧化酶（一种活性氧产生酶）可降低 AD小鼠毛细血管停滞的发生率在这里，建议从AD和中提取脑内皮细胞。野生型小鼠有和没有NAPDH氧化酶抑制，并使用RNA测序来确定这四组之间的基因表达差异不过分。将利用提取和加工过程中激活内皮细胞的工作来澄清细节。炎症反应的研究对于确定阻止这种效应的潜在药物靶点至关重要长期来看，可以改善患者的脑血流量，全身抑制中性粒细胞粘附。很难管理副作用，而这些基因表达数据将有助于确定干预的地方这项工作扩展了最初提案的目标 2，旨在确定导致 AD 小鼠毛细血管停滞增加的分子信号传导。