| 摘要 |
The invention disclosed herein describes a novel therapeutic target for motoneuron diseases (altered dynamics of microtubules and microtubule-mediated axonal transport of cargo molecules in neurons), with or without dementia, and in dementia; methods for measuring the state of activity of this therapeutic target in subjects with established, incipient, or potential motoneuron disease, with or without dementia, and in dementia; the discovery of drug agents that modulate neuronal microtubule dynamics in living subjects with motoneuron diseases; the discovery that administration of such agents, alone or in combinations, can improve MT-mediated transport of cargo molecules along and through axons; the discovery that such modulation of altered microtubule dynamics and improvement in MT-transport of molecules along axons can provide marked neuroprotective therapy for living subjects with motoneuron diseases, including delay in symptoms and prolongation of survival; and the discovery that monitoring of microtubule-mediated axonal transport of cargo molecules in response to therapeutic interventions in subjects with motoneuron diseases, with or without dementia, and in dementia allows diagnostic monitoring, to optimize therapeutic regimens and treatment strategies in individual subjects or in drug trials. |
| 主权项 |
1. A method of monitoring the effects of an agent in subjects with a motoneuron disease, with or without dementia, or a dementia (Alzheimer's disease) comprising:
a) exposing a test living system to one or more agents; b) administering an isotope-labeled substrate to said living system for a period of time sufficient for said isotope-labeled substrate to enter into one or more cargo molecules in axons of motor neurons or other subpopulations of neurons; c) obtaining a plurality of samples from said living system; d) quantifying the time course, pattern or amount of isotopic enrichment in one or more secreted vesicle cargo molecules from said plurality of samples; e) measuring the time course, pattern or amount of isotopic enrichment in secreted vesicle cargo molecules in a sample from a control system; f) comparing the time course, pattern or amount of isotopic enrichment in said isolated vesicle cargo molecules in said living system to the same parameters in a control living system; and g) determining the effect of said agent on the rate of microtubule (MT)-mediated slow and fast axonal transport in motor neurons or other subpopulations of neurons. |
