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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美国黑人最常见的隐性遗传性血液病之一镰状细胞病是由β-珠蛋白（β-珠蛋白）突变引起的。珠蛋白）基因，导致血红蛋白异常。镰状细胞病患者长期患有由于血红蛋白S的携氧能力降低而导致缺氧，引起短暂性缺血发作和多器官功能障碍血管闭塞后的低灌注导致血液不足供应到大脑，导致无氧代谢，从而激活炎症反应。不令人惊讶的是，镰状细胞病相关的血管性痴呆可能是普遍的。镰状细胞病可以减少记忆和认知功能，包括注意力持续时间缩短、空间功能和阅读。这些病理学被认为是由镰状细胞病脑引起的血管阻塞引起的。血管功能不全可导致脑血流自动调节功能丧失和认知功能受损与慢性脑缺氧有关总的来说，镰状细胞病的这些神经后遗症反映了血管痴呆和阿尔茨海默病及相关痴呆（ADRD）的相似性。由于这些相似性，我们比较了镰状细胞病和ADRD的病因，并检查了它们的共同机制。血管性痴呆的相关事件。我们最初发现，蛋白质精氨酸甲基转移酶（PRMT 4）在老化的3xTg- 这使得年龄依赖性PRMT 4成为一种新的相关靶点， ADRD。更重要的是，PRMT 4在雌性Townes小鼠（镰状细胞病模型）中增加，导致 PRMT 4在镰状细胞病中的后续研究。据我们所知，这是PRMT 4首次已在镰状细胞病（汤斯小鼠）中发现。众所周知，镰状细胞病可以引发血管闭塞危象，可加重脑灌注不足并扰乱脑血流。我们寻求确定PRMT 4介导的神经炎症标志物，以防止城镇中的血脑屏障破坏个脑袋因此，我们的中心假设是抑制PRMT 4（TP-064或PRMT 4-AAV）可以增强一氧化氮（NO），信号传导、神经血管耦合并保留老年汤斯雌性小鼠的功能性学习/记忆。我们描述了PRMT 4抑制作为对抗镰状细胞病相关血管性痴呆的治疗潜力。