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，由于失去伴侣而随着年龄的增长而加剧， 家庭脱节和社交网络的缩小。然而，随着COVID-19大流行持续， 在社交距离缩短的时期，社交孤立已成为一种普遍现象。因此，迫切需要 阐明社会隔离（SI）的生理影响和随后对伤害或疾病的脆弱性。 中风是全球死亡的主要原因，并且是心血管相关死亡的六分之一的原因。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， 康复过程需要病人花很多时间进行物理和职业治疗， 家庭成员、丧失行动能力和语言障碍。因此，虽然中风患者的社会孤立 经常在恢复期进行研究，16，17最近的一项研究表明，由于中风死亡的风险是 当比较中风前最孤立的患者和最不孤立的患者时， 一项研究提出了一个总体假设，即先前的社会隔离（SI）介导了中风恶化 将测试结果。近期目标是确定（如果有的话）既往SI和卒中严重程度的性别差异。 长期目标是了解既往SI影响卒中严重程度的机制，并提出一种治疗方法。 减轻先前SI的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。 - 子目标1a：研究既往SIS影响急性卒中后结局的假设。 - 子目标1b：研究既往SIS导致卒中后认知障碍的假设。 目的2：检验卒中结局因先前的社会隔离压力（SIS）而加重的假设， 适应不良的细胞变化和中枢神经系统的炎症。 - 子目标2a：检验既往SIS增加卒中诱导的血脑屏障通透性的假设。 - 子目标2b：检验先前的SIS将诱导神经炎症状态的假设，其中小胶质细胞和神经胶质细胞的表达增加。 星形胶质细胞被激活，导致中风结果恶化。 考虑到大多数人口在整个COVID-19期间经历的广泛隔离， 在大流行中，考虑既往SIS对卒中的长期影响至关重要。这些发现推动了我们的 了解和认识COVID-19对未来的影响。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与我成为一名医生的目标非常吻合 神经学领域的科学家本申请中描述的程序在 实验室，试验数据是我在学习这些技术的过程中获得的。