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.

项目概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影响 70,000-100,000 人。镰状细胞病是由 β-珠蛋白 (p- 球蛋白）基因，导致镰状细胞病患者长期患有血红蛋白异常。血红蛋白 S 携氧能力下降导致缺氧，导致短暂性脑缺血发作和血管闭塞后的多器官功能障碍导致血液不足。供给大脑导致无氧代谢，从而激活炎症反应。令人惊讶的是，镰状细胞病相关的血管性痴呆可能会减少。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。病理被认为是由镰状细胞病大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丧失和认知功能受损总而言之，镰状细胞病的这些神经系统后遗症与血管疾病有关。痴呆症与阿尔茨海默病和相关痴呆症 (ADRD) 的相似之处，由于这些相似之处，我们。比较了镰状细胞病和 ADRD 的病因，并检查了这些疾病的共同机制血管性痴呆中相互关联的事件。我们最初发现蛋白质精氨酸甲基转移酶 (PRMT4) 在老年 3xTg- AD 小鼠与较年轻的邻居相比，这使得年龄依赖性 PRMT4 成为对抗 AD 小鼠的新颖且相关的靶点更重要的是，PRMT4 在雌性 Townes 小鼠（一种镰状细胞病模型）中增加，从而导致 ADRD。 PRMT4在镰状细胞病中的后续研究据我们所知，这是PRMT4的首次研究。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。血管闭塞危象会加剧大脑灌注不足并扰乱脑血流。识别 PRMT4 介导的神经炎症标记物以防止汤斯血脑屏障破坏因此，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，并保留老年汤斯雌性小鼠的功能学习/记忆。将 PRMT4 抑制描述为针对镰状细胞病相关血管性痴呆的治疗潜力。