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

• 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
• 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

 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(申请人提供)：ABCD1对X连锁肾上腺脑白质营养不良症患者脑内皮细胞的影响PI：Patricia L.Musolino，M.D.，Ph.D.Musolino博士是马萨诸塞州总医院(MGH)获得董事会认证的儿童和神经危重护理神经病学家，哈佛医学院(HMS)讲师。Musolino博士的研究兴趣在于将人类遗传学的发现转化为X连锁肾上腺脑白质营养不良(ALD)和相关神经源性疾病的临床应用。利用她在分子神经科学方面的博士论文工作和正在进行的神经成像和血脑屏障(BBB)体外建模的博士后培训，Musolino博士将在指导项目和结构化教育活动的基础上 精通以下新的研究领域：(1)神经成像技术在生物标记物选择、疾病预测和风险分层方面的新应用；(2)设计实验性的体外分析，以测量单基因对血脑屏障生物学的影响；(3)从事翻译遗传学研究，以利用体内神经成像衍生参数的见解，在体外测试单基因的影响；以及(5)掌握先进的统计学和神经流行病学方法，这些方法对于测试神经源性疾病干预措施的有效性和有效性的临床研究的设计至关重要。X-连锁肾上腺脑白质营养不良(ALD)是一种由ABCD1基因突变引起的破坏性神经疾病，其特征是超长链脂肪酸的积累在美国影响1：17,000人。大约60%的ALD男性患者会转化为毁灭性的快速进行性炎性脱髓鞘形式，导致植物状态或在2-3年内死亡。ALD患者临床护理面临的一个重要挑战是缺乏强大的预测工具和模型系统。不幸的是，目前针对弥漫性代谢或造血细胞矫正的治疗方法要么无法预防脑部疾病，要么毒性很高。长期以来，血脑屏障受损一直被认为是疾病进展的关键，初步数据表明，白质动态磁化率对比(DSC)MR灌注降低先于病变进展。基于这些观察和体外初步工作，Musolino博士假设，白质BBB通透性的增加可以在病变进展之前通过DSC MR灌流检测到，这是脑内皮细胞缺乏功能性ABCD1的结果。为了验证这一假说，Musolino博士将从组织和分子水平探讨ABCD1缺乏对血脑屏障完整性的影响，方法包括：(1)应用新的DSC MR灌注算法，确定ALD患者脑白质微血管通透性的局部变化是否发生在病变进展之前(Aim 1)；(2)在体外评估ABCD1缺乏对人脑微血管内皮细胞屏障功能的影响(Aim 2)。如果被这项研究证实，Musolino博士的方法提出了一种成功的策略：(1)建立与表型转换有关的机制；(2)确定哪些患者有患脑部疾病的风险；(3)监测和改进我们目前的治疗方法；(4)开发一种检测方法，以筛选新的治疗靶点。Musolino博士的多学科导师团队包括脑白质营养不良专家Florian Eichler博士和高级功能神经成像领域的世界领先者Bruce Rosen博士，以及具有互补专业知识的合作者和资深教职员工，他们将指导这项研究，并在过渡期间促进她的职业发展，成为一名独立研究员。