Sex differences in the effects of prior social isolation stress on stroke outcomes

先前的社会孤立压力对卒中结果影响的性别差异

• 批准号: 10752478
• 负责人: Macy Zardeneta
• 金额: $ 3.63万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752478
• 关键词: Acute; Acute Disease; Adhesives; Adult; Affect; Age; Animals; Area; Astrocytes; Awareness; Biological; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Brain Infarction; CCL3 gene; COVID-19; COVID-19 pandemic; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Line; Cells; Central Nervous System; Cessation of life; Chronic Disease; Data; Dementia; Dextrans; Disease; Dose; Endothelin-1; Excision; Family; Family member; Female; Flow Cytometry; Fluorescein-5-isothiocyanate; Forelimb; Future; General Population; Goals; Histologic; Histology; Hour; Housing; Human; Immune; Impaired cognition; Incidence; Infarction; Inflammation; Inflammatory; Injury; Intravenous; Ischemic Stroke; Label; Learning; Long-Term Effects; Magnetic Resonance Imaging; Matrix Metalloproteinases; Measurement; Measures; Mediating; Memory; Microglia; Minocycline; Mission; Modeling; National Institute of Neurological Disorders and Stroke; Nervous System; Neurology; Obesity; Occupational Therapy; Outcome; Patient Isolation; Patients; Perfusion; Persons; Phagocytosis; Pharmaceutical Preparations; Phase; Physical therapy; Physicians; Physiological; Population; Procedures; Process; Proteins; Protocols documentation; RANTES; Rattus; Recovery; Research; Risk; Scientist; Serum; Severities; Sex Differences; Social Distance; Social Network; Social isolation; Stress; Stroke; Survivors; TLR4 gene; Techniques; Testing; Tight Junctions; Training; Vibrissae; Weight; Work; blood-brain barrier permeabilization; brain health; clinically relevant; cytokine; dementia risk; experience; glial activation; inhibitor; intraperitoneal; language impairment; male; middle age; mortality; mortality risk; nervous system disorder; neuroinflammation; novel; object recognition; physical process; post stroke; post stroke cognitive impairment; sex; social; stressor; stroke model; stroke outcome; stroke patient; therapeutic target; vasoconstriction

Project Summary Social isolation increases risk of all-cause mortality and chronic diseases such as obesity, cardiovascular disease, dementia, and stroke.12,13 A lack of social connectedness, or isolation, is exacerbated with age due to partner loss, family disconnect, and a narrowing of social networks. However, with the ongoing COVID-19 pandemic and long periods of social distancing, social isolation has become a widespread phenomenon. As such, it is urgent to elucidate the physiological effects of social isolation (SI) and subsequent vulnerability to injury or disease. Stroke is a leading cause of death worldwide and is the cause of 1 in 6 cardiovascular related deaths. Ischemic stroke accounts for over 80% of overall incidence.14,15 Social isolation after stroke is of clinical relevance due to the recovery process requiring patients to spend many hours in physical and occupational therapies away from family members, loss of mobility, and language impairment. Thus while social isolation in stroke patients has often been studied during the recovery period,16,17 a recent study showed that the risk of death due to stroke was higher when comparing the most isolated patients to the least isolated patients prior to stroke.18 In the following proposed studies the overarching hypothesis that prior-social isolation (SI) mediates worsened stroke outcomes will be tested. The immediate goal is to identify, if any, sex differences in prior-SI and stroke severity. The long-term goal is to understand the mechanism by which prior-SI affects stroke severity and propose a potential therapy for mitigating harmful effects of prior-SI. This will be studied in the following 3 aims: Aim 1: To investigate the effect of pre-stroke social isolation on stroke severity and outcome. -Sub-Aim 1a: To investigate the hypothesis that prior-SIS worsens acute post-stroke outcomes. -Sub-Aim 1b: To investigate the hypothesis that prior SIS worsens post-stroke cognitive impairment. Aim 2: To test the hypothesis that stroke outcomes are exacerbated by prior social isolation stress (SIS) due to maladaptive cellular changes and inflammation in the central nervous system. -Sub Aim 2a: To test the hypothesis that prior-SIS increases stroke-induced blood brain barrier permeability. -Sub Aim 2b: To test the hypothesis that prior-SIS will induce a neuroinflammatory state in which microglia and astrocytes become activated, leading to worsened stroke outcomes. Considering the extensive isolation undergone by the majority of the population throughout the COVID-19 pandemic, it is critical to consider the long-term effects of prior-SIS on stroke. These findings advance our understanding and awareness of the future implications of COVID-19. This training plan's focus on elucidating the effects of stressors on brain health and vulnerability to disease fit well with my goal of becoming a physician scientist in the field of neurology. The procedures described in this application are well established in the sponsor's lab, and the pilot data was acquired by me while learning these techniques.

项目摘要 社会隔离增加了全因死亡和慢性疾病的风险，如肥胖、心血管疾病、 痴呆症和中风。12，13缺乏社会联系或孤立，随着年龄的增长，由于失去伴侣而加剧， 家庭脱节，以及社交网络的缩小。然而，随着新冠肺炎大流行的持续和长时间的 在社会疏远时期，社会孤立已经成为一种普遍现象。因此，当务之急是 阐明社会隔离(SI)的生理效应以及随后对伤害或疾病的易感性。 中风是世界范围内主要的死亡原因，也是六分之一的心血管相关死亡的原因。缺血型 中风占总发病率的80%以上。14、15中风后的社会隔离具有临床相关性，原因是 康复过程需要患者花很多小时进行物理和职业治疗，远离 家庭成员、行动不便和语言障碍。因此，尽管中风患者的社交隔离有 经常在恢复期进行研究，16，17最近的一项研究表明，中风死亡的风险是 中风前隔离程度最高的患者与隔离程度最低的患者相比更高。18 提出的研究主要假设是先前的社会隔离(SI)会导致中风恶化 结果将受到考验。眼前的目标是确定性别差异，如果有的话，在先前的SI和卒中严重程度。 长期目标是了解先期SI影响卒中严重程度的机制，并提出 减轻Pre-SI有害影响的潜在疗法。这将在以下3个目标中进行研究： 目的1：探讨卒中前社会隔离对卒中严重程度和预后的影响。 -次级目标1a：调查先前的SIS会恶化急性卒中后预后的假设。 -次级目标1b：调查先前的SIS会加重中风后认知障碍的假设。 目的2：验证先前的社会隔离压力(SIS)会加重中风预后的假说 中枢神经系统中适应性不良的细胞变化和炎症。 -子目标2a：验证Pre-SIS增加中风引起的血脑屏障通透性的假设。 -子目标2b：测试先前-SIS将诱导神经炎症状态的假设，在这种状态下，小胶质细胞和 星形胶质细胞被激活，导致中风预后恶化。 考虑到新冠肺炎上的大多数人都经历了广泛的孤立 在大流行期间，考虑先期SIS对卒中的长期影响是至关重要的。这些发现推动了我们的 理解并意识到新冠肺炎的未来影响。这项培训计划的重点是阐明 应激源对大脑健康和疾病易感性的影响非常符合我成为一名医生的目标。 神经学领域的科学家。此应用程序中描述的过程在 赞助商的实验室，试验数据是我在学习这些技术时获得的。