Vascular Mechanisms of Dementia: Cell-Type Specific Therapeutic and Imaging Strategies

痴呆症的血管机制：细胞类型特异性治疗和成像策略

• 批准号: 10523230
• 负责人: Jaime Grutzendler
• 金额: $ 235.27万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523230
• 关键词: 3-Dimensional; Affect; Alzheimer' s Disease; Animal Model; Biological Assay; Biological Markers; Biology; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain imaging; Calcium; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Chemicals; Chemistry; Chronic; Cognitive; Cytoprotective Agent; Data; Dementia; Development; Endothelial Cells; Endothelium; Gene Expression; Generations; Goals; Hybrids; Image; Investigation; Iron; Iron Chelating Agents; Iron Chelation; Lead; Maintenance; Mediating; Metals; Microscopy; Microvascular Dysfunction; Modeling; Nerve Degeneration; Optics; Oxidation-Reduction; Pathogenesis; Pathology; Pericytes; Permeability; Pharmacology; Prevalence; Property; Reaction; Reactive Oxygen Species; Regulation; Resolution; Role; Signal Pathway; Smooth Muscle Myocytes; Specificity; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Vascular Endothelium; Vasomotor; analog; base; blood-brain barrier disruption; blood-brain barrier permeabilization; brain tissue; cell type; cerebral hypoperfusion; chemical synthesis; cytotoxicity; experimental study; hypoperfusion; imaging biomarker; imaging probe; improved; in vivo; innovation; intravital imaging; iron metabolism; microvascular pathology; multidisciplinary; neurovascular; non-invasive optical imaging; novel; pre-clinical; preclinical study; senescence; single-cell RNA sequencing; solute; targeted imaging; therapeutic target; tomography; transcriptomics; treatment response; uptake

ABSTRACT: Neuropathological studies in dementia frequently show mixed features including classical Alzheimer's hallmarks, cerebral amyloid angiopathy (CAA), microhemorrhages, and microinfarcts, highlighting the complexity and importance of vascular mechanisms in neurodegeneration. The precise mechanisms leading to CAA, microvascular degeneration, and dysregulated cerebral blood flow (CBF) are poorly understood. The cellular constituents of blood vessels include endothelial and mural cells (smooth muscle cells or pericytes), all of which have critical roles in CBF regulation and blood-brain barrier maintenance. While these cells are prominently affected in neurodegeneration, there are currently no specific therapeutic strategies for protecting them. A key objective of this application is to develop innovative strategies to therapeutically target and image the various vascular cellular components to improve our understanding of mechanisms leading to dementia. Specifically, we aim to complete proof-of-concept studies with a focus on potential mechanisms of cytotoxicity mediated by iron metabolism/reactive oxygen species (ROS) that may lead to microvascular degeneration. We aim to develop and test compounds that can preferentially target brain pericytes, smooth muscle cells, and endothelial cells with the goal of reducing intracellular free iron and ROS toxicity and ameliorating microvascular degeneration. These cell-type specific compounds will also be tested to determine their potential to be used as probes for deep tissue brain imaging in preclinical studies. To achieve this, we have assembled a multidisciplinary team at the interface of neurovascular biology and chemistry and propose a comprehensive set of experiments that combine intravital brain microscopy, chemical synthesis, single-cell transcriptomics, and animal models of CAA and microvascular pathology. This project has the potential for identifying targets and strategies for ameliorating microvascular degeneration that could significantly impact our mechanistic understanding and therapeutic approaches for vascular dementia.

摘要： 痴呆症的神经病理学研究经常显示出混合特征，包括经典的阿尔茨海默氏症标志， 脑淀粉样血管病（CAA），微血管病和微梗死，突出了复杂性， 血管机制在神经变性中的重要性。导致CAA的确切机制， 微血管变性和脑血流量失调（CBF）的认识很少。蜂窝 血管的成分包括内皮细胞和壁细胞（平滑肌细胞或周细胞），所有这些细胞都 在CBF调节和血脑屏障维护中发挥关键作用。虽然这些细胞在 在神经变性中受影响，目前没有保护它们的特异性治疗策略。一个关键 本申请的目的是开发创新的策略，以治疗性地靶向和成像各种 血管细胞成分，以提高我们对导致痴呆症的机制的理解。我们特别 旨在完成概念验证研究，重点关注铁介导的细胞毒性的潜在机制 代谢/活性氧（ROS）可能导致微血管变性。我们的目标是开发 以及可以优先靶向脑周细胞、平滑肌细胞和内皮细胞的测试化合物， 目的是降低细胞内游离铁和ROS毒性，改善微血管变性。这些 还将测试细胞类型特异性化合物，以确定它们用作深部组织探针的潜力 临床前研究中的脑成像。为了实现这一目标，我们在接口处组建了一个多学科团队 并提出了一套全面的实验，联合收割机结合活体 脑显微镜，化学合成，单细胞转录组学，CAA和微血管动物模型 病理该项目有可能确定改善微血管的目标和策略， 退化，可能会显着影响我们的机械理解和治疗方法， 血管性痴呆