Progressive Post Stroke Cognitive Impairment:Mechanisms & Intervention

进行性中风后认知障碍：机制

• 批准号: 10468083
• 负责人: ADVIYE ERGUL
• 金额: $ 46.32万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468083
• 关键词: Acute; Adult; Agonist; Angiotensin II Receptor; Angiotensins; Animals; Area; Astrocytes; Attenuated; Behavior assessment; Blood Vessels; Brain-Derived Neurotrophic Factor; Caring; Cells; Cerebrum; Cessation of life; Chronic; Cognitive; Cognitive deficits; Communication; Coupling; Data; Dementia; Deterioration; Development; Diabetes Mellitus; Disease; Endothelial Cells; Evolution; FDA approved; Female; Gliosis; Goals; Growth Factor; Hyperemia; Hypertension; Impaired cognition; Impairment; In Vitro; Incidence; Inflammatory; Intervention; Ischemic Stroke; Knowledge; Lesion; Mediating; Microglia; NGFR Protein; Neurons; Outcome; Patients; Pattern; Pharmacology; Phase; Phenotype; Publishing; Rattus; Research; Signal Transduction; Stroke; Stroke prevention; Synaptic plasticity; Testing; Therapeutic; Time; United States; Vascular Cognitive Impairment; Vascularization; Work; acute stroke; aged; angiogenesis; base; cognitive function; comorbidity; cost; diabetic; diabetic rat; disability; experience; genetic manipulation; hypertensive; improved; loss of function; male; mortality; neovascularization; neuron loss; neuroprotection; neurovascular unit; normotensive; novel; novel therapeutic intervention; novel therapeutics; overexpression; post stroke; post stroke cognitive impairment; prevent; receptor; restoration; small hairpin RNA; stroke patient; stroke victims; therapeutic target; therapy development

ABSTRACT: Vascular cognitive impairment /dementia (VCID) is one of the most disabling consequences of stroke, occurring in 12%-48% of patients. At a time when stroke mortality is decreasing, the rate of VCID after stroke almost doubled between 1990 and 2000, increasing the urgency for treatment development in this area. A critical barrier to progress in the development of new therapeutic strategies is the lack of understanding of how VCID develops after stroke. The use of almost exclusively male and healthy animals in experimental stroke research has widened this gap in knowledge. Our exciting preliminary data demonstrated a progressive deterioration of cognitive function after experimental stroke, an impairment accentuated by the presence of comorbid diseases such as hypertension and diabetes. We also show the presence of an extended therapeutic window to prevent VCID. Recent data from the REGARDS study showed that stroke patients also experience a progressive cognitive decline after a single lesion stroke, causing us to rethink how we approach VCID therapeutically. Accordingly, the goal of this proposal is to define the cellular mechanisms contributing to the chronic build-up of cognitive deficits after stroke. Based on the strong scientific premise of our published and pilot data, our central hypothesis is that progressive cognitive decline is profound when stroke is superimposed on comorbid diseases and involves microglial activation leading to decreased mature brain derived neurotrophic factor (mBDNF) signaling and remodeling in the neurovascular unit. We further hypothesize that Angiotensin type II receptor (AT2) stimulation disrupts this perpetual inflammatory loop and prevents progressive VCID. 3 integrated translational and mechanistic aims will test these hypotheses; Aim 1: progressive cognitive deficits after stroke, augmented in comorbid conditions, CAN be therapeutically targeted. Aim 2: microglia that are activated to M1-like phenotype after stroke in comorbid disease states, amplify dysregulation of BDNF signaling leading to NVU remodeling and ultimately, progressive VCID. Aim 3: AT2 stimulation prevents progressive VCID by promoting M2-like microglial activation and restoration of BDNF signaling in NVU cells. In 10 studies over 5 years, and utilizing rigorous behavioral assessment of aged, hypertensive, and diabetic animals, pharmacologic and genetic manipulation, novel gain and loss-of-function approaches, as well as in vitro assessment, we will advance our understanding of the treatment of VCID, an understudied yet devastating consequence of ischemic stroke.

摘要：血管性认知障碍/痴呆（VCID）是卒中最严重的致残性后果之一，发生在12%-48%的患者中。在卒中死亡率下降的同时，卒中后VCID的发生率在1990年至2000年期间几乎翻了一番，增加了该领域治疗开发的紧迫性。在开发新的治疗策略方面取得进展的一个关键障碍是缺乏对中风后VCID如何发展的理解。在实验性中风研究中几乎完全使用雄性和健康的动物扩大了这一知识差距。我们令人兴奋的初步数据表明，实验性卒中后认知功能进行性恶化，这种损害因高血压和糖尿病等共病而加重。我们还显示存在延长的治疗窗口，以防止VCID。REGARDS研究的最新数据显示，中风患者在单处病变中风后也会出现进行性认知下降，这使我们重新思考如何治疗VCID。因此，本提案的目标是确定有助于中风后认知缺陷慢性积累的细胞机制。基于我们已发表和试点数据的强有力的科学前提，我们的中心假设是，当卒中叠加于共病疾病时，进行性认知下降是深刻的，并且涉及小胶质细胞活化，导致成熟脑源性神经营养因子（mBDNF）信号传导减少和神经血管单元重塑。 我们进一步假设血管紧张素II型受体（AT 2）刺激破坏了这种永久性炎症循环，并防止进行性VCID。3个整合的转化和机制目标将测试这些假设;目标1：卒中后进行性认知缺陷，在共病条件下加重，可以作为治疗靶点。 目标二：在共病状态下中风后被激活为M1样表型的小胶质细胞放大了BDNF信号传导的失调，导致NVU重塑并最终导致进行性VCID。 目的3：AT 2刺激通过促进NVU细胞中M2样小胶质细胞活化和BDNF信号转导的恢复来防止进行性VCID。在超过5年的10项研究中，并利用对老年、高血压和糖尿病动物的严格行为评估、药理学和遗传操作、新的功能获得和丧失方法以及体外评估，我们将推进对VCID治疗的理解，VCID是缺血性卒中的一种未充分研究但具有破坏性的后果。