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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

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