Effect of ABCD1 upon Brain Endothelium in X-linked Adrenoleukodystrophy



 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.