MicroRNAs, Mitochondria and the Blood-Brain Barrier - Therapeutic Targets for Stroke

MicroRNA、线粒体和血脑屏障——中风的治疗靶点

• 批准号: 10587899
• 负责人: Xuefang Sophie Ren
• 金额: $ 45.34万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587899
• 关键词: Acute; Affect; Autopsy; Bioenergetics; Blood - brain barrier anatomy; Brain; Brain Injuries; Cell Survival; Cognitive deficits; Complex; Data; Databases; Development; Disease; EF Hand Motifs; Elderly; Electron Transport; Endothelial Cells; Endothelium; Filament; Functional disorder; Genes; Glucose; Goals; Hemorrhage; Human; Impairment; In Vitro; Infarction; Integral Membrane Protein; Ischemia; Ischemic Stroke; Knock-out; Knockout Mice; Leucine Zippers; Magnetic Resonance Imaging; Maintenance; Measures; Mediating; Membrane Potentials; Messenger RNA; MicroRNAs; Middle Cerebral Artery Occlusion; Mitochondria; Mitochondrial Membrane Protein; Modeling; Molecular; Motor; Mouse Strains; Mus; Oxidative Phosphorylation; Oxygen; Persons; Plasma; Play; Production; Proteins; Recovery of Function; Research; Role; Sampling; Stroke; Structure; Testing; Therapeutic; Transfection; Translational Repression; Vascular Cell Adhesion Molecule-1; aged; aging brain; blood-brain barrier disruption; blood-brain barrier permeabilization; brain tissue; cell age; cerebrovascular; cognitive testing; comparison control; deprivation; effective therapy; experimental study; functional outcomes; human old age (65+); improved; improved outcome; in vitro Model; in vivo; in vivo Model; inhibitor; mitochondrial membrane; motor function improvement; nanoparticle; nanoparticle delivery; novel; novel therapeutics; overexpression; pre-clinical; sex; stroke model; stroke outcome; stroke patient; therapeutic target

Project Summary/Abstract Stroke is a debilitating disease, affecting >15 million people worldwide annually, the majority of which are over 65 years old. Developing effective treatments for older stroke patients remains a pressing need. Stroke causes disruption of the blood-brain barrier (BBB) to brain damage, hemorrhagic transformation (HT), and worse functional outcomes. We have discovered that mitochondrial energy production in cerebrovascular endothelial cells (CECs) plays a central role in maintenance of BBB integrity both in in vivo and in vitro models. We have found altered levels of several microRNAs (miRNAs) in plasma and primary CECs (pCECs) from aged stroke mice. Specifically, expression of miR-34a is upregulated in both the plasma and pCECs from aged stroke mice compared with sham controls. Notably, miR-34a is also upregulated in plasma from stroke patients compared to healthy controls. Overexpression of miR-34a in murine CECs (mCECs) increases BBB permeability, compromises mitochondrial oxidative phosphorylation (OxPhos), and reduces mitochondrial membrane potential (ΔΨm) while decreasing the levels of several mitochondrial related genes; Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) in human CECs (hCECs) and LETM domain containing 1 (LETMD1) in mCECs. Importantly, our preliminary data show that LETM1 is significantly reduced in CECs in autopsy samples from stroke patients compared with controls. Additionally, we have shown that global knockout of miR-34a (miR- 34a–/–) reduces infarct size and conversely, overexpression of miR-34a (miR-34aTG) increases infarct size in mice. Similarly, systemic delivery of antagomiR-34a (a miR-34a inhibitor) reduces infarct size and improves long-term functional recovery in stroke mice. Although our findings provide compelling evidence that miR-34a plays an important role in stroke pathophysiology, the mechanism by which endothelial miR-34a mediates brain damage is unknown, especially in aged models of stroke. The objective of this proposal is to investigate if endothelial specific miR-34a affects stroke outcomes in the aged brain. We hypothesize that endothelial miR-34a regulates BBB permeability, ischemic damage, hemorrhagic transformation, and stroke-induced deficits by inhibiting translation of LETM1 and LETMD1 leading to impaired mitochondrial bioenergetics in CECs. Aim 1 will test if endothelial specific knockout of miR-34a improves acute and long-term stroke outcomes in aged mice of both sexes. Aim 2 will identify a mechanism by which miR-34a inhibits translation of LETM1 and LETMD1 leading to impaired mitochondrial function in CECs following stroke. Aim 3 will determine the therapeutic potential of nanoparticle delivery of endothelial cell targeted miR-34a antagomir in aged stroke mice of both sexes. Our studies will elucidate the role of endothelial miR-34a in stroke. Understanding the preclinical effects of endothelial specific antagomiR-34a treatment is an important step in the development of novel therapies for elderly stroke patients.

项目总结/文摘