Effect of ABCD1 upon Brain Endothelium in X-linked Adrenoleukodystrophy

ABCD1 对 X 连锁肾上腺脑白质营养不良脑内皮的影响

基本信息

批准号：
9149035
负责人：
Patricia Leonor Musolino
金额：
$ 19.34万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9149035
关键词：
Adhesions Adrenoleukodystrophy Affect Algorithms Animal Model Area Biological Assay Biological Markers Biological Models Biology Blood - brain barrier anatomy Brain Caring Cell Adhesion Molecules Cells Cerebrum Cessation of life Child Clinical Research Data Defect Demyelinations Development Diffuse Disease Disease Progression Doctor of Medicine Doctor of Philosophy Educational Activities Effectiveness of Interventions Endothelial Cells Endothelium Experimental Designs Extravasation General Hospitals Genes Hematopoietic Histopathology Human Human Genetics Image In Vitro Individual Inflammation Inflammatory Inherited Laboratories Lead Lesion Leukocytes Magnetic Resonance Imaging Manuscripts Massachusetts Measures Mentors Metabolic Metalloproteases Methods Microvascular Permeability Molecular Monitor Mus Mutation Neurologist Neurosciences Patients Perfusion Permeability Phenotype Plasma Predisposition Preparation Proteins Research Research Personnel Risk Secondary to Specimen Stratification Structure System Techniques Testing Therapeutic Intervention Tight Junctions Time Tissues Toxic effect Translations Vegetative States Very Long Chain Fatty Acid Work base biomarker selection brain endothelial cell career development cell type cerebral degeneration clinical application clinical care design drug candidate efficacy testing high risk improved in vitro Assay in vitro Model in vivo insight instructor interest leukodystrophy male medical schools member migration monocyte mortality multidisciplinary myelin degeneration nervous system disorder neuroimaging new therapeutic target novel novel therapeutics overexpression post-doctoral training predictive modeling predictive tools prevent public health relevance screening senior faculty tool translational genetics white matter

项目摘要

DESCRIPTION (provided by applicant): Effect of ABCD1 upon Brain Endothelium in X-linked Adrenoleukodystrophy PI: Patricia L. Musolino, M.D., Ph.D. Dr. Musolino is board-certified child and neurocritical care neurologist at the Massachusetts General Hospital (MGH) and instructor in at the Harvard Medical School (HMS). Dr. Musolino's research interest lies in the translation of discoveries in human genetics to clinical application in X-linked Adrenoleukodystrophy (ALD) and related neurogenic disorders. Leveraging her PhD thesis work in molecular neuroscience and ongoing postdoctoral training in neuroimaging and in- vitro modeling of the blood brain barrier (BBB), Dr. Musolino will build on mentored project and structured educational activities to gain proficiency in the following new research areas: (1) Novel applications of neuroimaging techniques for biomarker selection, disease prediction, and risk stratification; (2) Design experimental in-vitro assays to measure the impact of single genes upon BBB biology; (3) Pursue research in translational genetics to leverage insights from in-vivo neuroimaging-derived parameters to test single gene effects in-vitro; and (5) Master advanced statistical and neuroepidemiology methods vital for the design of clinical studies that test efficacy and effectiveness of interventions in neurogenic disorders. X-linked adrenoleukodystrophy (ALD) is a devastating neurologic disorder caused by mutations in the ABCD1 gene characterized by the accumulation of very long-chain fatty acids that affects 1:17,000 individuals in the U.S. Approximately 60% of male patients with ALD will convert to a devastating rapidly progressive form of inflammatory demyelination that leads to a vegetative state or death within 2-3 years. An important challenge facing clinical care of patients with ALD is the lack of robust predictive tool and model systems. Unfortunately current treatments targeting diffuse metabolic or hematopoietic cell correction either fails to prevent cerebral disease or carry high toxicity. BBB disruption has for a long time been implicated as crucial to disease progression, and preliminary data suggests that decreased dynamic susceptibility contrast (DSC) MR perfusion in the white matter precedes lesion progression. Based on these observations and preliminary work in-vitro Dr. Musolino hypothesizes that increases in white matter BBB permeability can be detected with DSC MR Perfusion prior to lesion progression and are the result of the lack of functional ABCD1 in brain endothelium. To test this hypothesis Dr. Musolino will probe the effect of ABCD1 deficiency upon BBB integrity at both the tissue and molecular level by (1) Applying new DSC MR perfusion algorithms to determine if regional changes in white matter microvascular permeability occur prior to lesion progression in patients with ALD (Aim 1) and; (2) Evaluating in-vitro the effects of lack of ABCD1 upon the barrier function of human brain microvascular endothelial cells (Aim 2). If validated by this study, Dr. Musolino's approach sets forth a successful strategy to: (1) establish mechanisms involved in the phenotypic conversion; (2) identify which patients are at risk of developing cerebral disease; (3) monitor and improving our current treatments and; (4) develop an assay to screen for novel therapeutic targets. Dr. Musolino's multidisciplinary team of mentors include Dr. Florian Eichler, expert in leukodystrophies, and Dr. Bruce Rosen, world leader in advanced functional neuroimaging, as well as collaborators and senior faculty members with complementary expertise that will guide this research and promote her career development during the transition to become an independent investigator.

描述（由适用提供）：ABCD1对X连锁adnerukodyrophrophy pi的脑内皮的影响：Patricia L. Musolino，M.D。，Ph.D。 Musolino博士是马萨诸塞州综合医院（MGH）的董事会认证的儿童和神经关注神经科医生，哈佛医学院（HMS）的讲师。 Musolino博士对人类遗传学发现转化为X连锁性肾上腺素肌营养不良（ALD）和相关神经源性疾病的临床应用的研究兴趣。 Musolino博士利用她在分子神经科学和正在进行的神经影像学和体外模型中正在进行的神经影像学和体外建模（BBB）中的博士学位论文工作的工作，Musolino博士将在受过指导的项目和结构化的教育活动上建立在以下新研究领域获得熟练程度：（1）神经成像技术在生物标志物选择，疾病预测和风险分层中的新应用；（2）设计实验性体内评估，以衡量单个基因对BBB生物学的影响；（3）从事转化遗传学的研究以利用体内神经影像学参数的见解来测试视野内的单个基因效应；（5）主要的晚期统计和神经性电子学方法对于设计神经源性疾病的有效性和有效性的临床研究至关重要。 X连锁的肾上腺肾上腺营养不良（ALD）是由ABCD1基因突变引起的毁灭性神经系统疾病，其特征是在美国，在美国大约60％的男性患者中有1：17,000名患者的积累，大约60％的ALD患者会迅速转化为抗抑素的炎症形式，在炎症中造成了较快的疾病状态，这些疾病是在2次或植物中造成的，而植物性或植物性却是植物性或植物性的植物性疾病。 ALD患者临床护理面临的一个重要挑战是缺乏可靠的预测工具和模型系统。不幸的是，针对弥漫性代谢或造血细胞矫正的目前治疗方法不能预防脑病或毒性高。长期以来，BBB的破坏已被认为是疾病进展至关重要的，初步数据表明，在白质中，动态敏感性对比度改善了动态敏感性对比度（DSC）MR灌注，先于病变进展。基于这些观察结果和初步工作，Musolino博士假设在病变进展之前，可以用DSC MR灌注来检测白质BBB渗透性的增加，这是脑内皮中缺乏功能性ABCD1的结果。为了检验这一假设，Musolino博士将通过（1）探测ABCD1缺乏症对组织和分子水平上BBB完整性的影响（1）应用新的DSC MR灌注算法以确定白质微血管渗透性的区域变化是否在ALD患者中发生在病变之前（AIM 1）和; AIM 1）和; （2）评估体外的ABCD1缺乏对人脑微血管内皮细胞屏障功能的影响（AIM 2）。如果通过这项研究证实，Musolino博士的方法将成功地提出了一种成功的策略：（1）建立与表型转化有关的机制；（2）确定哪些患者有患脑病的风险；（3）监控和改善我们当前的治疗方法；（4）制定评估以筛选新的治疗靶标。 Musolino博士的跨学科导师团队包括Liukodystrophies专家Florian Eichler博士和高级功能性神经影像学的世界领导者Bruce Rosen博士，以及具有完整专业知识的合作者和高级教职员工，这些专业知识将指导这项研究并在过渡期间成为独立研究员的职业发展并促进她的职业发展。