Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common genetic disease caused by mutations in the gene NF1. Most NF1 pediatric patients present with diverse neurological conditions, including learning disabilities, attention deficit and hyperactivity disorder (ADHD), and motor skill issues. No specific treatments for these issues are available and most patients perform poorly in school. Brain white matter (WM) and myelin abnormalities are commonly observed in parallel with the peak of neurological conditions in NF1, yet no clear evidence can link abnormal myelin and brain dysfunction in NF1. This represents a critical barrier to progress in the NF1 field. In contrast, evidence of central roles for myelin in regulating learning and mood is rapidly increasing. Hence, this project’s goal is to use the most recent information and tools on myelin biology to unveil specific impacts of Nf1 mutation on oligodendrocyte (OL; brain myelinating cell) / myelin development and related brain dysfunction. Understand- ing mechanisms for Nf1 mutation in mouse models will diversify therapeutic tools and schedules for NF1 treat- ments. Indirect evidence suggests roles for Nf1 in every step of OL formation and myelin development, and our preliminary results suggest transiently increased brain WM/myelin in infants with NF1. Moreover, life-long anal- yses in Nf1+/- mice suggest hyperproliferation of OL precursors (OPCs) and increased OL production in postna- tal development and, contrastingly, defective OPC proliferation in adults. Correlatively, juvenile Nf1+/- mice show increased activity and learning in a myelin regulated motor skill test (complex wheel; CW), and impaired activ- ity/learning in 1-year old Nf1+/- mice. These mice, however, have Nf1 mutated in every cell; thus, to unveil links between Nf1-driven abnormal myelin biology and brain function we propose using myelin specific models. We hypothesize that postnatally induced Nf1 mutation in OPCs increases their proliferation/differentiation, which causes transient hyperactivity and improved learning curves of fine motor skills in the CW test. To test this idea, we will use a tamoxifen inducible system to mutate Nf1 in mouse OPCs (nNf1). The Aim 1 will define the OL lineage progression in nNf1 mice, Aim 2 will test nNf1 impact on CW activity and learning, and Aim 3 will assess the rescue of phenotypes. Successful completion of these aims will help to settle a long-lasting debate on myelin- behavior links in NF1. In the mid-term, results will help to propose therapeutic targets and windows of time for interventions in NF1 patients. In line with NIH mission, this study will generate fundamental neuroscience knowledge and promote reduction of the burden of neurological diseases, particularly of NF1 on pediatric pa- tients. The PI’s expertise and research network in NF1, myelin biology, and mouse genetics will be essential for the timely completion of the aims. Furthermore, this study involves direct participation of undergraduate minority- in-science students and will produce data for high impact publications to achieve research excellence.
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