Eleanor and Lou Gehrig MDA/ALS Research Center Projects Proposal Funded by MDA's Wings Over Wall Street® 2006 Fund Raising
Hiroshi Mitsumoto, MD	Oxidative Stress in ALS	$67,580	To complete the current MDA- funded genetic-epidemiology study. To initiate an ambispective case-control study of oxidative stress in ALS. To study biomarkers of oxidative stress with exercise in patients with ALS, compared with controls. To investigate if exercise stress test can be used as a tool to develop oxidative stress biomarkers.
Paul Gordon, MD Hiroshi Mitsumoto, MD	Phase II Combination Drug Selection Trial	$56,031	Compare the neuroprotective potential of two combinations of agents that influence different mechanisms of neurodegeneration in an ongoing phase II trial Obtain Magnetic Resonance Spectroscopy on a subset of patients to determine brain penetration of an agent Obtain plasma riluzole levels to determine whether the drug combinations alter riluzole metabolism Acquire data from patients in year 2 of the trial Maintain accurate and clean data in a database designed specifically for the trial Analyze, prepare publications, and report the trial results. Design a phase III multicenter clinical trial based on the results
Robert Basner, MD Hiroshi Mitsumoto, MD Paul Gordon, MD	Persistence of Impaired Nocturnal Ventilation in ALS Using Non-Invasive Positive Pressure	$68,454	Continuation of above cross sectional study with projected total of 30 patients for full description of prevalence and severity of nocturnal oxygenation and ventilatory failure in ALS patients using prescribed NIPPV over a range of pulmonary function status Describe the major secondary endpoints (physiologic and demographic factors) thought likely to influence the primary outcome measures, including ventilator settings, gender; age at onset of diagnosis; duration of the disorder; body mass index; type of ALS (bulbar vs. limb onset); rapidity of disease progression, quality of life and functional assessment (ALSFRS-R); co-morbidities; and riluzole use.
Paul Gordon, MD Karen Marder, MD	Longitudinal Study of Cognitive Impairment in ALS	$56,031	Fully enroll patients in a longitudinal study, collecting data on cognitive dysfunction from a large population of patients with ALS. Obtain and store DNA samples to analyze genetic risks for cognitive impairment in ALS Obtain autopsy from a subset of patients to obtain clinic-anatomic correlation on patients with ALS and cognitive impairment Create a database and enter data from 60 patients studied serially. Determine indicators of prognosis, the clinical impact of changes in cognition, and best measures of cognitive impairment in this population. Reach a definition of dementia and cognitive impairment in ALS. Analyze data, prepare publications and report findings from the study. Prepare NIH applications to study cognitive impairment in ALS from a population-based sample.
Christopher Henderson, Ph.D.	Mechanisms of motor neuron cell death in ALS	$51,000	Pursue new strategy for creating mice in which all motor neurons will express luciferase in their nucleus and fluorescent protein in their axons Validate luciferase levels as a reliable reporter of motor neuron numbers in adult spinal cord Breed reporter mice to ALS model mice to determine location and timing of motor neuron loss during the course of the disease
Thomas Jessell, PhD	Loss of Cxcr Signaling Results in Virtually Complete Denervation of the Diaphragm	$51,000	Focused on innervation of the diaphragm muscle Use a motor neuron specific Cre recombinase line (Olig2:Cre) to inactivate Cxcr4 selectively in motor neurons, and examine the impact on innervation of the diaphragm. Examine the role and mechanisms of Cxcr4 signaling in motor innervation patterns Explore the possibility that mice carrying a mutant SOD1 allele exhibit disruptive Cxcr4 signaling.
Serge Przedborski, MD, PhD,	ER stress and NOGO pathway	$51,000	Determine the molecular machinery involved in SOD1 entry in the ER Assess the effects of modulating the expression of ER chaperon on cell survival Examine the impact of up-regulation of ER chaperon on mutant SOD1 turnover