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.

项目概要 社会隔离会增加全因死亡和肥胖、心血管疾病等慢性疾病的风险， 痴呆和中风。12,13 由于失去伴侣，社会联系的缺乏或孤立会随着年龄的增长而加剧。 家庭关系脱节，社交网络缩小。然而，随着新冠肺炎 (COVID-19) 疫情的持续蔓延和长期 在社会疏远时期，社会孤立已成为一种普遍现象。因此，当务之急是 阐明社会孤立（SI）的生理影响以及随后对伤害或疾病的脆弱性。 中风是全世界死亡的主要原因，六分之一的心血管相关死亡是由中风引起的。缺血性 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意义，因为 康复过程需要患者花费大量时间进行物理和职业治疗，远离 家庭成员、行动能力丧失和语言障碍。因此，虽然中风患者的社会隔离 经常在恢复期进行研究，16,17 最近的一项研究表明，中风导致的死亡风险是 将中风前最孤立的患者与最不孤立的患者进行比较时，该值更高。18 拟议的研究总体假设是先前的社会隔离（SI）会导致中风恶化 结果将受到检验。近期目标是确定既往 SI 和中风严重程度的性别差异（如果有）。 长期目标是了解既往 SI 影响中风严重程度的机制，并提出一种 减轻既往 SI 有害影响的潜在疗法。对此，我们将围绕以下3个目标进行研究： 目标 1：调查中风前社会隔离对中风严重程度和结果的影响。 -子目标 1a：调查既往 SIS 使中风后急性结局恶化的假设。 -子目标 1b：调查既往 SIS 使中风后认知障碍恶化的假设。 目标 2：检验以下假设：先前的社会隔离压力 (SIS) 会加剧中风结果，原因是 中枢神经系统适应不良的细胞变化和炎症。 -子目标 2a：检验先前 SIS 增加中风引起的血脑屏障通透性的假设。 -子目标 2b：检验先前 SIS 会诱发神经炎症状态的假设，其中小胶质细胞和 星形胶质细胞被激活，导致中风结果恶化。 考虑到大多数人在 COVID-19 期间经历了广泛的隔离 大流行期间，考虑先前的 SIS 对中风的长期影响至关重要。这些发现推进了我们的 了解和认识 COVID-19 的未来影响。本培训计划的重点是阐明 压力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 神经病学领域的科学家。本申请中描述的程序已在 赞助商的实验室，试验数据是我在学习这些技术时获得的。