Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a tragic and fatal neurodegenerative disorder that results from the loss of nerve cells that control muscle function. There are certain proteins produced during development that are known to promote growth of these cells. One such protein is brain-derived neurotophic factor (BDNF). It was initially thought that the effects of BDNF may have therapeutic potential for slowing the progression of ALS. However, recent clinical trials have surprisingly revealed that administration of BDNF accelerated ALS disease progression in patients. Follow- up studies have actually implicated BDNF in predisposing adult motor neurons to die. Therefore, identifying mechanisms that quench BDNF-mediated signaling may be of significant therapeutic interest in the case of ALS. Perhaps the most straight forward strategy in preventing BDNF-induced cell death is by using small-molecules with drug-like properties. We recently identified one such molecule. Preliminary results indicate that this compound is able to inhibit BDNF from binding to its receptor preventing the molecular events thought to contribute to ALS progression. These promising results lead us to the hypothesis that small-molecule BDNF inhibitors can prevent nerve cell death in ALS. Thus the studies set forth in this application propose to evaluate the therapeutic potential of small-molecule BDNF-inhibitors for preventing never death, and the results may lead to new treatments for ALS.