PPIL4 modulation of Notch links neurovascular malformation to brain aneurism

PPIL4对Notch的调节将神经血管畸形与脑动脉瘤联系起来

• 批准号: 10094262
• 负责人: Stefania Nicoli
• 金额: $ 36.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094262
• 关键词: Adult; Affect; American; Aneurysm; Animals; Arteries; Biological Assay; Biological Models; Blood; Blood Vessels; Brain; Brain Injuries; Brain Vascular Malformation; Brain hemorrhage; Cause of Death; Cell Culture Techniques; Cells; Cerebrovascular system; Chemicals; Complex; Data; Defect; Diagnosis; Diffusion; Disease; Epidemiology; Event; Extravasation; Family; Fishes; Functional disorder; Future; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Hemorrhage; Histopathology; Human; Impairment; Intervention; Intracranial Aneurysm; Intracranial Hemorrhages; Laboratories; Larva; Lead; Lesion; Link; Long-Term Care; Mediating; Microscopy; Modeling; Molecular; Morphogenesis; Mus; Mutation; Neurologic; Notch Signaling Pathway; Organism; Outcome; Outcome Study; Oxygen; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Pharmacology; Phenotype; Predictive Factor; Predisposition; Probability; Proteins; Public Health; Regulation; Research; Risk; Risk Factors; Role; Rupture; Signal Pathway; Signal Transduction; Signaling Protein; Sudden Death; Symptoms; System; Tertiary Protein Structure; Testing; Therapeutic; Transforming Growth Factor beta; Variant; Zebrafish; cell type; disability; experience; experimental study; genetic approach; genetic manipulation; genetic variant; human model; improved; in vivo; loss of function; malformation; mutant; neurosurgery; neurovascular; neurovascular unit; new therapeutic target; notch protein; novel; novel strategies; prevent; screening; tool

Summary Intracranial Aneurism (IA) is a disease in which weakened blood vessels in the brain bulge and fill with blood, often leading to rupture, brain hemorrhage and sudden death. Strikingly, people with intracranial aneurism don't manifest obvious symptoms even minutes before hemorrhage, making preventative diagnosis and treatment obsolete. Up to 10% of the general population has a high probability of carrying a brain aneurism, revealing a serious burden to public health. Every year, 30,000 people in the U.S. alone experience brain hemorrhages that cause death or brain damage requiring long-term care. Since the exact cause(s) of brain aneurism remains elusive, the only hope for these patients is to first, identify risk factors predictive of the vascular lesion in the brain and second, find a strategy to prevent the bleeding events. Although genetic predispositions for aneurisms has been discovered in multiple families, whether the mutations associated with IA directly cause the disease is unknown. The objective of our proposal is to understand the cellular and molecular events that lead to brain vessel fragility, with the long-term goal of uncovering new approaches to treat and prevent IA. To determine whether candidate mutations cause IA and uncover their pathological mechanisms, we will utilize a powerful zebrafish model system that uniquely recapitulates the loss of function of the PPIL4 gene, which variants are strongly associated with IA. We plan to apply sophisticated cellular and genetic manipulation of our zebrafish model to discover how PPIL4 mutations affect Notch signaling to trigger vessel rupture, and how to prevent this outcome. Specifically, we propose to study how PPIL4 controls the interaction between neurovascular cells (Aim 1), how PPIL4 functions in healthy fish to promote the stability of the Notch intracellular domain (Aim 2) and examine if genetic and chemical strategies can prevent vascular leakage in the ppil4+/- model (Aim 3). The outcome of this study will help to elucidate the requirement of this novel gene in the neurovascular system and to understand how human PPIL4 mutations may cause vascular defects and susceptibility to IA.

总结 颅内动脉瘤（IA）是一种大脑中弱化的血管膨胀并充满血液的疾病， 经常导致破裂、脑出血和猝死。引人注目的是，患有颅内动脉硬化症的人 即使在出血前几分钟也没有表现出明显的症状， 治疗过时。高达10%的普通人群有很高的可能性携带脑萎缩症， 这对公共卫生造成了严重的负担。每年，仅在美国就有3万人 导致死亡或需要长期护理的脑损伤。由于大脑的确切原因 糖尿病仍然难以捉摸，这些患者的唯一希望是首先确定预测糖尿病的风险因素。 第二，找到预防出血事件的策略。虽然遗传 在多个家庭中发现了遗传易感性，无论与遗传易感性相关的突变是否 IA的直接病因尚不清楚。我们的建议的目的是了解细胞和 导致脑血管脆弱性的分子事件，长期目标是发现新的方法， 治疗和预防IA。 为了确定候选突变是否导致IA并揭示其病理机制，我们 将利用一个强大的斑马鱼模型系统，该系统独特地再现了PPIL 4基因功能的丧失， 这些变体与IA密切相关。我们计划将复杂的细胞和基因 操纵我们的斑马鱼模型，以发现PPIL 4突变如何影响Notch信号传导，从而触发血管 破裂，以及如何防止这种结果。具体而言，我们建议研究PPIL 4如何控制相互作用 在神经血管细胞之间（目的1），PPIL 4如何在健康鱼类中发挥作用，以促进Notch的稳定性 细胞内结构域（目标2），并检查遗传和化学策略是否可以防止血管渗漏， ppil 4 +/-模型（目标3）。这项研究的结果将有助于阐明这种新基因在 神经血管系统，并了解人类PPIL 4突变如何导致血管缺陷， 对IA的敏感性。