权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Modeling and Therapeutic Approaches for Genetic Vasculopathies

遗传性血管病的建模和治疗方法

基本信息

批准号：
10706537
负责人：
MARK E LINDSAY
金额：
$ 69.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706537
关键词：
Actins Adolescent Affect Age Alleles Anesthesia procedures Animal Model Aorta Aortic Aneurysm Arginine Arteries Behavioral Biological Models Bladder Blood Blood Pressure Blood Vessels Blood flow Brain Brain Infarction Bundling CRISPR/Cas technology Cardiovascular Diseases Carotid Arteries Cell Line Cell model Cell physiology Cellular Assay Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Characteristics Child Childhood Clinical Clustered Regularly Interspaced Short Palindromic Repeats Collagen Complex Custom DNA Sequence Alteration Data Deposition Development Diagnosis Dilatation - action Disease Disease Progression Dominant-Negative Mutation Elasticity Elastin Evaluation Exhibits Eye Functional disorder Gene Targeting Genes Guide RNA Heterozygote Histidine Histopathology Home Homeostasis Hypotension Impaired cognition Impairment In Vitro Infarction Intestines Ipsilateral Ischemia Ischemic Stroke Knock-in Knock-out Lead Life Ligation LoxP-flanked allele Lung Measures Mediating Medical Microvascular Dysfunction Modeling Molecular Mus Muscle Mutation Mydriasis Natural History Neurologic Neurology Operative Surgical Procedures Organ Oxygen Patent Ductus Arteriosus Pathogenicity Pathology Patient observation Patients Performance Pericytes Phenotype Prevention Publishing Pupil Rare Diseases Recurrence Rupture Shapes Smooth Muscle Smooth Muscle Myocytes Stroke Stroke prevention Study models Syndrome System Systemic blood pressure Therapeutic Uterus Variant Vascular Diseases Woman adeno-associated viral vector base editing body system brain abnormalities cerebrovascular disability early onset experience functional outcomes gene correction gene therapy genetic approach human disease improved in vivo mortality mouse model mutant neurovascular neurovascular coupling novel palliate pre-clinical predictive marker respiratory secondary endpoint vascular abnormality white matter injury

项目摘要

Summary Smooth Muscle Dysfunction Syndrome is a rare disease with less than 50 known cases worldwide. It is caused by a specific genetic mutation in the ACTA2 gene that affects smooth muscle cells. Smooth muscle cells are found in many different organs in the body. These include the large blood vessels that carry blood around the body (aorta), brain blood vessels, lungs, eye pupil muscles, gut, bladder and even the womb in women. The children affected by this specific ACTA2 mutation have very complex medical problems involving many body systems. Patients experience repeated strokes as blood vessels supplying the brain are abnormal in shape and narrowed. As adolescents, the aorta can weaken and dissect, requiring major surgery. Some children have need respiratory support or home oxygen. These children suffer from a severe complex disease that can result in progressive neurological disability. Our aim is to develop a gene therapy for children with ACTA2 disease that can treat all the different organs affected. In this proposal we will extensively characterize in vitro ACTA2R179H smooth muscle cell function (AIM1), evaluate the neurovascular and subsequent behavioral consequences of the ACTA2R179H mutation in a novel mouse model (AIM2), and finally use the ACTA2R179H mouse model to study the ischemic strokes (AIM3). To investigate therapeutic options throughout the proposal we will utilize a novel CRISPR-cas9 system with custom guide RNAs to revert (base editing) or destroy (allele targeting) the ACTA2R179H allele, delivering the system in vitro and in vivo, and quantitatively measuring the phenotypic consequences of gene targeting

总结