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

基本信息

批准号：
10546468
负责人：
Stefania Nicoli
金额：
$ 36.64万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10546468
关键词：
Adult Affect American Aneurysm Animals Applied Genetics 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 Collaborations Complex Data Defect Diagnosis Diffusion Disease Environmental Risk Factor Epidemiology Event Extravasation Family Fishes Functional disorder Future General Population Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Goals Hemorrhage Heterozygote 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 Persons Pharmaceutical Preparations Phenotype Population 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 pharmacologic prevent screening tool

项目摘要

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.

概括颅内动脉症（IA）是一种疾病通常导致破裂，脑出血和猝死。令人惊讶的是，患有颅内动脉瘤的人甚至在出血前几分钟都不会表现出明显的症状，进行预防性诊断和治疗过时。多达10％的普通人群具有携带大脑动脉症的可能性很高，揭示了对公共卫生的严重负担。每年，仅美国就有30,000人会体验到大脑导致死亡或脑部损伤需要长期护理的出血。由于大脑的确切原因动脉瘤仍然难以捉摸，对这些患者的唯一希望是首先确定预测的风险因素大脑中的血管病变，其次，找到一种防止出血事件的策略。虽然遗传在多个家庭中发现了动脉瘤的易感性，是否与之相关的突变 IA直接引起该疾病是未知的。我们建议的目的是了解细胞和导致脑血管脆弱性的分子事件，其长期目标是发现新方法治疗并预防IA。为了确定候选突变是否引起IA并发现其病理机制，我们将利用强大的斑马鱼模型系统，该系统独特地概括了PPIL4基因的功能丧失，哪些变体与IA密切相关。我们计划应用复杂的细胞和遗传操纵我们的斑马鱼模型，以发现PPIL4突变如何影响Notch信号传导以触发血管破裂，以及如何防止这种结果。具体而言，我们建议研究PPIL4如何控制相互作用在神经血管细胞之间（AIM 1），PPIL4如何在健康鱼类中起作用以促进缺口的稳定性细胞内结构域（AIM 2）并检查遗传和化学策略是否可以防止血管泄漏 PPIL4 +/-模型（AIM 3）。这项研究的结果将有助于阐明该新基因的需求神经血管系统，并了解人类PPIL4突变如何导致血管缺陷和对IA的敏感性。