Grant: $140,131 - National Institutes of Health - Aug. 17, 2009
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Award Description: In higher vertebrates, nerve conduction is greatly facilitated by myelin, a lipid-rich membrane that wraps around the axon. Myelin is formed by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). A number of devastating demyelinating diseases threaten human health, and few effective treatments exist. To develop better treatment for these diseases, we must understand the mechanisms involved in myelination. The overall goal of our ongoing study is to elucidate pathways for the synthesis of unique myelin lipids and their roles in myelination and cell signaling, with particular emphasis on 2-OH lipids. The specific objective of the ARRA award is to extend the study to include animal behavioral studies to gain further insight into the role of 2-OH lipids in myelination and myelin function in mice. A fatty acid 2-hydroxylase (FA2H) is responsible for the biosynthesis of myelin 2-OH lipids. We recently developed an Fa2h knockout mouse model, which allows as to investigate specific alterations in myelination and myelin function caused by the loss of 2-OH lipids. We have learned that Fa2h knockout mice do not develop any visible signs of neurological deficits for the most of their lives in their home cages with no stress. This is in striking contrast to the human disorder caused by mutations in the FA2H gene. Patients with FA2H deficiency presented with gait disturbance due to lower-limb spasticity at 4-6 years of age. The disease is restricted to the lower limbs with no cognitive or speech impairment in two patients from one family. In contrast, the disease rapidly progressed in seven patients from other two families. They required walking aids at 7 years age and presented with spasticity extended to the upper limbs; dystonia involving trunk, limbs, and face; upper-motor neuron deficits; decline in cognitive abilities; cerebellar dysfunction. Thus, it became necessary to perform additional behavioral analyses to uncover any potential neurological deficits of Fa2h knockout mice in order to fully understand the function of Fa2h in the mouse. These analyses would also help define the utility and limitation of Fa2h knockout mouse model as a disease model for FA2H deficiency. The ARRA award enabled us to conduct behavioral studies (motor coordination, locomotor activity, and spatial memory) to uncover neurological deficits of Fa2h knockout mice. The neurological deficits of the mice found in this study could be utilized to test potential therapeutics for human FA2H deficiency.
Project Description: As defined in the Award Description field
Jobs Summary: Postdoc Scholar (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Aug. 17, 2009. Help expand these official descriptions using the wiki below.