Protein arginine methyltransferase-mediated vascular dementia in sickle cell disease

镰状细胞病中蛋白质精氨酸甲基转移酶介导的血管性痴呆

基本信息

批准号：
10662136
负责人：
Hung Wen (Kevin) Lin
金额：
$ 217.65万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662136
关键词：
3xTg-AD mouse Abnormal Hemoglobins Affect African American population Age Alzheimer&apos s disease related dementia Attention Blood - brain barrier anatomy Blood Vessels Brain Brain Diseases Brain Hypoxia Carrying Capacities Cells Cerebrovascular Circulation Chronic Clinical Coupled Depressed mood Development Diameter Discrimination Enzymes Erythrocytes Etiology Event Family Female Functional disorder Genes Genotype Globin Health Care Costs Hematological Disease Heme Hemoglobin Hemoglobin SS High Prevalence Homeostasis Immunity Impaired cognition Individual Inflammation Inflammatory Response Inherited Investigation Ischemic Stroke Knockout Mice Knowledge Laser Scanning Microscopy Laser Speckle Imaging Learning Measures Mediating Mediator Memory Metabolism Modality Modeling Mus Mutation N,N-dimethylarginine Neurologic Nitric Oxide Obstruction Organ Outcome Measure Oxygen Pathology Pathway interactions Patient Care Patients Plasma Protein Inhibition Protein Methyltransferases Protein-Arginine N-Methyltransferase Reading Role Shapes Sickle Cell Anemia Sickle Hemoglobin Signal Transduction Texture Thalassemia Therapeutic Time Transient Ischemic Attack United States Vascular Dementia Vascular blood supply Vibrissae age related aged beta Globin cognitive function cytotoxicity deprivation dimethylargininase functional outcomes hemoglobin polymer hypoperfusion inhibitor knock-down life time cost neuroinflammation neurovascular neurovascular coupling novel object recognition preservation prevent sex sickling two-photon vaso-occlusive crisis

项目摘要

Project Summary Sickle cell disease is one of the most common recessive inherited blood disorders in African Americans affecting 70,000-100,000 individuals in the U.S. Sickle cell disease is caused by mutations in the β-globin (p- globin) gene, which leads to hemoglobin abnormalities. Sickle cell disease patients chronically suffer from oxygen deprivation due to depressed oxygen-carrying capacity of hemoglobin S causing transient ischemic attacks, and multiple organ dysfunction. Hypoperfusion following vaso-occlusion leads to insufficient blood supply to the brain resulting in anaerobic metabolism, thus activating the inflammatory response. It is not surprising that sickle cell disease -related vascular dementia may be prevalent. Sickle cell disease can decrease memory and cognitive function including shortened attention spans, spatial function, and reading. These pathologies are thought to be caused by the vascular obstructions caused by the sickle cell disease brain. Vascular insufficiency can lead to loss of cerebral blood flow autoregulation and impaired cognitive function related to chronic brain hypoxia. Altogether, these neurological sequelae of sickle cell disease mirrors vascular dementia and similarities of Alzheimer's disease and related dementias (ADRD). Due to these similarities, we compared the etiologies of sickle cell disease and ADRD, and examined the common mechanism(s) of these inter-related events in vascular dementia. We originally discovered that protein arginine methyltransferases (PRMT4) is enhanced in aged 3xTg- AD mice v. younger counterparts, this makes the age-dependent PRMT4 a novel and relevant target against ADRD. More importantly, PRMT4 is increased in female Townes mice, a model of sickle cell disease, leading to subsequent investigations of PRMT4 in sickle cell disease. To our knowledge, this is the first time that PRMT4 has been identified in sickle cell disease (Townes mice). It is also well-known that sickle cell disease can trigger vaso-occlusive crisis that can exacerbate brain hypoperfusion and disturb cerebral blood flow. We seek to identify PRMT4-mediated neuroinflammatory markers to prevent blood brain barrier breakdown in the Townes brain. Therefore, our central hypothesis is inhibition of PRMT4 (TP-064 or PRMT4-AAV) can enhance nitric oxide signaling, neurovascular coupling, and preserve functional learning/memory in aged Townes female mice. We describe PRMT4 inhibition as a therapeutic potential against sickle cell disease-related vascular dementia.

项目摘要镰状细胞病是非裔美国人最常见的隐性遗传性血液疾病之一在美国镰状细胞疾病中影响70,000-100,000个个体是由β-珠蛋白突变引起的（p- Globin）基因，导致血红蛋白异常。镰状细胞病患者长期遭受由于血红蛋白S降低氧气的能力，导致短暂性缺血引起的氧气剥夺能力攻击和多个器官功能障碍。血管咬合后的灌注不足导致血液不足向大脑供应导致厌氧代谢，从而激活炎症反应。它不是令人惊讶的是，与镰状细胞疾病相关的血管痴呆可能很普遍。镰状细胞病可以减少记忆和认知功能，包括缩短注意力跨度，空间功能和阅读。这些人们认为病理是由镰状细胞疾病大脑引起的血管对象引起的。血管功能不全可能导致脑血流自动调节的损失和认知功能受损与慢性大脑缺氧有关。这些镰状细胞疾病的神经后遗症总共反映了血管阿尔茨海默氏病和相关痴呆症（ADRD）的痴呆症和相似之处。由于这些相似性，我们比较了镰状细胞疾病和ADRD的病因，并检查了这些病因血管性痴呆中相关事件。我们最初发现蛋白精氨酸甲基转移酶（PRMT4）在年龄的3xTG-中得到了增强 AD MICE诉年轻同行，这使得与年龄有关的PRMT4成为反对的新颖且相关的目标 adrd。更重要的是，雌性城镇小鼠的PRMT4增加了，这是一种镰状细胞疾病的模型，导致随后对镰状细胞疾病中PRMT4的研究。据我们所知，这是PRMT4首次已在镰状细胞病（城镇小鼠）中鉴定出来。众所周知，镰状细胞疾病会触发可以加剧脑部灌注并干扰脑血流量的血管结合性危机。我们寻求识别PRMT4介导的神经炎症标记，以防止城镇的血液屏障崩溃脑。因此，我们的中心假设是抑制PRMT4（TP-064或PRMT4-AAV）可以增强一氧化氮信号传导，神经血管耦合并保留老年小鼠老鼠的功能学习/记忆。我们将PRMT4抑制作用描述为针对镰状细胞疾病相关的血管痴呆的治疗潜力。