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 社会隔离会增加全因死亡率和慢性疾病的风险，例如肥胖，心血管疾病， 痴呆症和中风。12,13缺乏社会联系或孤立性，随着伴侣损失而导致的年龄加重， 家庭断开连接和社交网络的狭窄。但是，随着持续的19009大流行和长期 社会疏远，社会隔离的时期已成为一种普遍的现象。因此，迫切需要 阐明社会隔离（SI）的生理影响以及随后对伤害或疾病的脆弱性。 中风是全球死亡的主要原因，是六分之六的与心血管相关的死亡的原因。缺血性 中风占整体发病率的80％以上。14,15中风后的社会隔离是由于临床相关性 恢复过程要求患者在物理和职业疗法上花费数小时远离 家庭成员，流动性丧失和语言障碍。因此，尽管中风患者的社会隔离有 经常在恢复期间进行研究，16,17一项最近的研究表明，卒中死亡的风险是 将最孤立的患者与中风之前最不孤立的患者进行比较时。18在以下 拟议的研究总体假设，即先前的社会分离（SI）介导了中风恶化 结果将进行测试。直接目标是确定先前SI和中风严重性的性别差异（如果有）。 长期目标是了解先验SI影响中风严重程度的机制并提出 减轻先验SI有害影响的潜在疗法。这将在以下3个目标中进行研究： 目标1：研究中风前社会隔离对中风严重性和结果的影响。 -sub-aim 1a：调查以下假设，即先前的SIS会使急性势后结果恶化。 -sub-aim 1b：要研究以下假设：先前的SIS会使击球后认知障碍恶化。 目的2：检验以下假设，即因先前的社会隔离压力（SIS）加剧了中风结果 中枢神经系统中不良适应性细胞的变化和炎症。 -SUB AIM 2A：为了检验以下假设，即先前SI会增加中风引起的血脑屏障渗透性。 -Sub AIM 2B：检验以下假设：先前SIS将诱导小胶质细胞和 星形胶质细胞被激活，导致中风结果恶化。 考虑到整个Covid-19的大多数人口经历了广泛的隔离 大流行，至关重要的是考虑先前SIS对中风的长期影响。这些发现进步了 了解和认识COVID-19的未来影响。该培训计划的重点是阐明 压力源对大脑健康和疾病脆弱性的影响非常适合我成为医生的目标 神经病学领域的科学家。本应用程序中描述的程序已在 赞助商的实验室，并在学习这些技术时被我获取。