Effect of ABCD1 upon Brain Endothelium in X-linked Adrenoleukodystrophy

 描述（由申请人提供）：ABCD 1对X连锁肾上腺脑白质营养不良中脑内皮素的影响PI：Patricia L. Musolino，医学博士，博士Musolino博士是马萨诸塞州总医院（MGH）的董事会认证的儿童和神经重症监护神经学家，也是哈佛医学院（HMS）的讲师。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以及正在进行的神经成像和血脑屏障（BBB）体外建模方面的博士后培训，Musolino博士将在指导项目和结构化教育活动的基础上， 在以下新的研究领域获得熟练程度：（1）神经成像技术的生物标志物选择，疾病预测和风险分层的新应用;（2）设计实验性体外测定，以测量单基因对BBB生物学的影响;（3）追求翻译遗传学研究，以利用体内神经成像衍生参数的见解来测试体外单基因效应;掌握先进的统计学和神经流行病学方法，这些方法对于设计临床研究至关重要，这些研究测试了神经源性疾病干预措施的功效和有效性。X-连锁肾上腺脑白质营养不良（ALD）是一种破坏性的神经系统疾病，由ABCD 1基因突变引起，其特征是非常长链脂肪酸的积累，影响美国1：17，000的个体。大约60%的男性ALD患者将转化为破坏性的快速进展形式的炎性脱髓鞘，导致植物人状态或在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，目前靶向弥散代谢或造血细胞校正的治疗不能预防脑疾病或具有高毒性。长期以来，BBB破坏被认为对疾病进展至关重要，初步数据表明，白色物质中动态磁敏感对比度（DSC）MR灌注降低先于病变进展。根据这些观察结果和体外初步工作，Musolino博士假设，在病变进展之前，可以通过DSC MR灌注检测到白色物质BBB渗透性增加，这是脑内皮缺乏功能性ABCD 1的结果。为了验证这一假设，Musolino博士将通过以下方式在组织和分子水平上探索ABCD 1缺乏对BBB完整性的影响：（1）应用新的DSC MR灌注算法来确定ALD患者中白色物质微血管通透性的区域变化是否发生在病变进展之前（目的1）;（2）体外研究ABCD 1缺失对人脑微血管内皮细胞屏障功能的影响（目的2）。如果这项研究得到验证，Musolino博士的方法提出了一个成功的策略：（1）建立参与表型转换的机制;（2）确定哪些患者有患脑疾病的风险;（3）监测和改善我们目前的治疗方法;（4）开发一种检测方法来筛选新的治疗靶点。Musolino博士的多学科导师团队包括脑白质营养不良专家Florian Eichler博士和高级功能性神经成像领域的世界领导者布鲁斯罗森博士，以及具有互补专业知识的合作者和高级教员，他们将指导这项研究并促进她在过渡期间成为独立研究者的职业发展。

 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.