The role of microglia Nek6 in myocardial infarction-induced cognitive impairment

小胶质细胞 Nek6 在心肌梗死所致认知障碍中的作用

• 批准号: 10713921
• 负责人: Partha Dutta
• 金额: $ 38.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713921
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease risk; Antibodies; Binding Sites; Biological Assay; Blood Vessels; Brain; CD80 gene; CD86 gene; Cardiovascular Diseases; Cd68; Cerebrovascular Disorders; Cognition; Confocal Microscopy; Consumption; Coronary artery; Data; Dementia; Deposition; Diabetes Mellitus; Disease; Epigenetic Process; Exercise; Exhibits; Flow Cytometry; Gene Activation; Genes; Heart failure; Hippocampus; Histone H1; Histone H3; Histone H4; Histones; Human; Human Amyloid Precursor Protein; Imaging Techniques; Impaired cognition; Inflammation; Inflammatory; Knock-in Mouse; Learning; Letters; Leukocytes; Ligation; Link; Memory; Memory impairment; Metabolic syndrome; Microglia; Molecular; Motor Activity; Mus; Myocardial Infarction; NIMA; Neurons; Obesity; Parabiosis; Patients; Phagocytes; Phenotype; Phosphorylation; Phosphotransferases; Play; Population; Proliferating; Promoter Regions; Psychosocial Stress; Regional Disease; Reporting; Risk; Risk Factors; Role; Senile Plaques; Smoking; Sorting; Source; Testing; Time; Transcription Alteration; Up-Regulation; Visit; apolipoprotein E-4; arm; cognitive function; dementia risk; experimental study; glial activation; intravital microscopy; monocyte; mouse model; nano-string; nanoparticle; novel; recruit; sham surgery; transcriptome; unhealthy lifestyle; vascular cognitive impairment and dementia; western diet

Various studies have reported that patients with heart failure (HF) have cognitive impairment. However, the molecular mechanisms behind this are not well understood. Mice carrying human APOE4, which is a risk factor for dementia in patients with cardiovascular disease, exhibited cognitive impairment after they developed HF. These mice also had heightened number of microglia compared to littermate non-HF control mice. The hippocampus, which is crucial to learning and memory, expressed high levels of disease-associated microglial genes such as Tspo and Tnfsf13b. Additionally, microglia in mice with HF upregulated Nek6, which phosphorylates histones H1 and H3, resulting in gene activation. Based on these preliminary data, we hypothesize that Nek6 upregulation in microglia in mice with heart failure exaggerates inflammation and impairs cognitive function. We will test this hypothesis in one specific aim. We will delineate the role of inflammation in cognitive impairment in HF (Aim 1.1). Hippocampal inflammation, distribution of leukocyte populations, microglial activation, source of excess microglia, amyloid plaque deposition, microglial phagocytic activity, and the role of Tspo in memory impairment in mice with HF will be evaluated. Furthermore, the contribution of Nek6 in epigenetic alterations in hippocampal microglia and memory dysfunction in mice with HF will be discerned (Aim 1.2).

各种研究已经报道，患有心力衰竭（HF）的患者具有认知损害。但 这背后的分子机制还没有很好地理解。携带人类APOE4的小鼠，这是一个危险因素 对于患有心血管疾病的痴呆患者，在发生HF后表现出认知障碍。 与同窝非HF对照小鼠相比，这些小鼠的小胶质细胞数量也增加。的 海马体，这是至关重要的学习和记忆，表达高水平的疾病相关的小胶质细胞， 例如Tspo和Tnfsf13b基因。此外，HF小鼠中的小胶质细胞上调Nek6， 磷酸化组蛋白H1和H3，导致基因激活。根据这些初步数据，我们 假设心力衰竭小鼠小胶质细胞中Nek6上调会加重炎症并损害 认知功能我们将在一个特定的目标中检验这一假设。我们将描述炎症在 HF中的认知损害（目标1.1）。海马炎症，白细胞群分布，小胶质细胞 激活，过量小胶质细胞的来源，淀粉样蛋白斑块沉积，小胶质细胞吞噬活性，以及 将评价Tspo在HF小鼠记忆障碍中的作用。此外，Nek 6在表观遗传学中的贡献 将发现HF小鼠中海马小胶质细胞和记忆功能障碍的改变（目标1.2）。

项目成果

Epidermal Growth Factor Receptor in Hepatic Endothelial Cells Suppresses MCP-1-Dependent Monocyte Recruitment in Diabetes.

肝内皮细胞中的表皮生长因子受体抑制糖尿病中 MCP-1 依赖性单核细胞的募集。

• DOI: 10.4049/jimmunol.2200557
• 发表时间: 2023
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Zhang,Xinyi;Ohayon-Steckel,Lee;Coppin,Emilie;Johny,Ebin;Dasari,Ankush;Florentin,Jonathan;Vasamsetti,Sathish;Dutta,Partha
• 通讯作者: Dutta,Partha

Left Coronary Artery Ligation: A Surgical Murine Model of Myocardial Infarction.

• DOI: 10.3791/64387
• 发表时间: 2022-08-09
• 期刊: Journal of visualized experiments : JoVE
• 作者: Johny E;Dutta P
• 通讯作者: Dutta P

VEGF Receptor 1 Promotes Hypoxia-Induced Hematopoietic Progenitor Proliferation and Differentiation.

• DOI: 10.3389/fimmu.2022.882484
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

The role of extracellular vesicles in regulating local and systemic inflammation in cardiovascular disease.

• DOI: 10.1016/j.phrs.2021.105692
• 发表时间: 2021-08
• 期刊: Pharmacological research
• 影响因子: 9.3
• 作者: Ohayon L;Zhang X;Dutta P
• 通讯作者: Dutta P

Peripheral Ischemia Imprints Epigenetic Changes in Hematopoietic Stem Cells to Propagate Inflammation and Atherosclerosis.

外周缺血会影响造血干细胞的表观遗传变化，从而传播炎症和动脉粥样硬化。

• DOI: 10.1161/atvbaha.123.318956
• 发表时间: 2023
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Coppin,Emilie;Zhang,Xinyi;Ohayon,Lee;Johny,Ebin;Dasari,Ankush;Zheng,KangH;Stiekema,Lotte;Cifuentes-Pagano,Eugenia;Pagano,PatrickJ;Chaparala,Srilakshmi;Stroes,ErikS;Dutta,Partha
• 通讯作者: Dutta,Partha