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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：
10335131
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335131
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 Persons 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

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.

总结