NOVA Scientific proposes to adapt a powerful new type of neutron diffraction instrumentation for biological applications, a neutron counting and imaging detector called the MCP/Medipix detector. The detector offers much higher spatial and timing resolution, as well as higher count rate capability (10-100 MHz) and dynamic range compared with existing neutron position-sensitive detectors. It was designed to provide state-of-the-art performance to match the higher neutron fluences of next generation of neutron scattering and imaging facilities. Although demonstrated successfully during the past year in other applications, this powerful new instrument has never been applied to research in cellular and structural biology. We propose for the first time to modify and employ it as new detector tool to elucidate biologically important structures by using it in neutron diffraction (ND). One highly promising biological system which could benefit would be myelin, the electrically insulating material that ensheathes the neuron axon; its integrity is critically important for the proper functioning of the nervous system. Myelin ultrastructure studies, traditionally carried out using electron microscopy and X-ray diffraction could be substantially enhanced by using a more powerful new type of neutron diffraction (ND) detector, particularly with the increasing availability of a variety of transgenic mice that model human demyelinating disorders. Myelin would be an ideal test case for demonstrating the MCP/Medipix detector, as it allows benchmarking of previous ND measurements carried out with 3He detectors. This will demonstrate that that the improved performance of the MCP/Medipix detector represents a major advance in the power of ND for cellular and structural biology. In Phase I neutron diffraction experiments will be carried out using mouse nerves for the first time anywhere, as there are numerous transgenic mice strains that mimic human myelinopathies in both the PNS and CNS. To accomplish this, assembly and integration of a neutron sensitive 40 mm MCP with a modified Medipix readout will be carried out, preparing it for high fluence neutron diffraction experiments on a biologically-oriented neutron diffractometer. Also a versatile and advanced perfusion cell will be constructed allowing deuteration of samples for enhanced contrast variation, and to minimize neutron scattering noise. Two ND diffraction test campaigns will be carried out with the MCP/Medipix detector. Different aspects of myelin ultrastructure will be illuminated to show feasibility of ND as an essential tool for answering specific questions about myelin structure and inter-membrane dynamics. A Phase II program would expand this initial feasibility study to build larger area format MCP/Medipix detectors with the addition of advanced neutron beam collimation, to obtain even greater neutron sensitivity and diffraction pattern resolution, as well as data collection speed and efficiency. Ultimately, the MCP/Medipix detector and collimator ND enhancement would be commercialized for the benefit of the biological ND community.
Public Health Relevance: This project develops new laboratory instrumentation to increase the power of neutron diffraction (ND), a highly sophisticated technique with the potential to probe far deeper into the actual structure of myelin, the electrically insulating material that ensheathes central core of nerve fibers. The integrity of myelin is critically important for the proper functioning of the nervous system; demyelinating disorders such as multiple sclerosis (MS), certain peripheral neuropathies, and leukodystrophies are characterized by the progressive disruption and breakdown with partial or attempted re-formation of the highly ordered myelin sheath. The ability to accurately measure these extremely subtle features of myelin, enabled by the new NOVA Scientific/Medipix detector, will increase our knowledge about disease states, and will help to provide insight into developing therapeutic strategies for stabilizing normal myelin or remyelinating nerve fibers.
Public Health Relevance Statement: This project develops new laboratory instrumentation to increase the power of neutron diffraction (ND), a highly sophisticated technique with the potential to probe far deeper into the actual structure of myelin, the electrically insulating material that ensheathes central core of nerve fibers. The integrity of myelin is critically important for the proper functioning of the nervous system; demyelinating disorders such as multiple sclerosis (MS), certain peripheral neuropathies, and leukodystrophies are characterized by the progressive disruption and breakdown with partial or attempted re-formation of the highly ordered myelin sheath. The ability to accurately measure these extremely subtle features of myelin, enabled by the new NOVA Scientific/Medipix detector, will increase our knowledge about disease states, and will help to provide insight into developing therapeutic strategies for stabilizing normal myelin or remyelinating nerve fibers.
NIH Spending Category: Autoimmune Disease; Bioengineering; Brain Disorders; Multiple Sclerosis; Neurodegenerative; Neurosciences
Project Terms: Area; Axon; base; Benchmarking; Biological; biological systems; Biology; Cells; Cellular biology; Collimator; Communities; Data Collection; Data Set; Demyelinating Diseases; design; detector; Disease; drug testing; Effectiveness; Electron Microscopy; Failure; Fatigue; Feasibility Studies; Future; Human; Image; imaging detector; improved; insight; instrument; instrumentation; Investigation; Knowledge; Laboratories; Leadership; leukodystrophy; Measurement; Measures; Medical; Membrane; Methods; Modeling; mouse model; Mouse Strains; Multiple Sclerosis; Mus; Myelin; Myelin Sheath; myelinopathy; Nerve; Nerve Fibers; Nerve Tissue; Nervous System Physiology; Neural Conduction; Neuraxis; Neurons; Neurosciences; Neutron Diffraction; Neutrons; next generation; Noise; Pattern; Performance; Perfusion; Peripheral Nervous System; Peripheral Nervous System Diseases; Phase; Physiological; Positioning Attribute; programs; Property; repaired; Research; Research Personnel; research study; Resolution; Sampling; Science; Screening procedure; Speed; Spinal cord injury; Stress; structural biology; Structure; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Time; time use; Tissue Sample; tool; Transgenic Mice; United States; Variant; Vertebrates; X ray diffraction analysis; X-Ray Diffraction
