Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron degenerative disease and is characterized by a progressive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. It can strike adults of any age, though is most common between the ages of 50-55 years. The molecular mechanisms that cause this disease are unclear and biomarkers specific for ALS are currently unknown. Our preliminary data using mass spectrometry based proteomics identified a panel of protein biomarkers from cerebrospinal fluid (CSF) with a high level of accuracy for diagnosing ALS near the time of clinical symptom onset. We propose to examine a much larger group of ALS and control subjects to further validate and identify protein based biomarkers for ALS. The goals of this proposal are to further explore the CSF proteome of ALS and control subjects to identify peptide and/or protein biomarkers for ALS. We will utilize liquid chromatography based mass spectrometry in a large unbiased screen for peptides that distinguish ALS from control subjects. We will then validate our findings in separate subject groups and generate a mass spectrometry based method to quantify specific peptides within the CSF and/or plasma that distinguish ALS from control subjects. We will then use this panel of biomarkers to distinguish sub- populations of ALS patients based on site of disease onset, age, gender, or rate of disease progression. These studies will generate novel biomarkers for ALS that could be used in future diagnostics for ALS and tested for their ability to monitor disease progression or drug efficacy in clinical trials.

Public Health Relevance

The molecular mechanisms underlying amyotrophic lateral sclerosis (ALS) are unclear and new research directions and hypotheses are necessary to generate novel therapeutic targets. Our proposal will uncover novel peptide and protein biomarkers for ALS. These studies will lead to new insights into disease mechanisms and potential diagnostic determinants for ALS that can be further explored in future studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061867-06
Application #
8470251
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Gubitz, Amelie
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$313,898
Indirect Cost
$107,026
Name
St. Joseph's Hospital and Medical Center
Department
Type
DUNS #
131606022
City
Phoenix
State
AZ
Country
United States
Zip Code
85013
Vu, Lucas T; Bowser, Robert (2016) Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis. Neurotherapeutics :
Liu, Xiaochen; Lu, Deyi; Bowser, Robert et al. (2016) Expression of Carbonic Anhydrase I in Motor Neurons and Alterations in ALS. Int J Mol Sci 17:
Li, Yang; Collins, Mahlon; An, Jiyan et al. (2016) Immunoprecipitation and mass spectrometry defines an extensive RBM45 protein-protein interaction network. Brain Res 1647:79-93
Li, Yang; Collins, Mahlon; Geiser, Rachel et al. (2015) RBM45 homo-oligomerization mediates association with ALS-linked proteins and stress granules. Sci Rep 5:14262
Bakkar, Nadine; Boehringer, Ashley; Bowser, Robert (2015) Use of biomarkers in ALS drug development and clinical trials. Brain Res 1607:94-107
Collins, Mahlon A; An, Jiyan; Peller, Danielle et al. (2015) Total protein is an effective loading control for cerebrospinal fluid western blots. J Neurosci Methods 251:72-82
Collins, Mahlon A; An, Jiyan; Hood, Brian L et al. (2015) Label-Free LC-MS/MS Proteomic Analysis of Cerebrospinal Fluid Identifies Protein/Pathway Alterations and Candidate Biomarkers for Amyotrophic Lateral Sclerosis. J Proteome Res 14:4486-501
Smith, Richard; Myers, Kathleen; Ravits, John et al. (2015) Amyotrophic lateral sclerosis: Is the spinal fluid pathway involved in seeding and spread? Med Hypotheses 85:576-83
Bakkar, Nadine; Kousari, Arianna; Kovalik, Tina et al. (2015) RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1. Mol Cell Biol 35:2385-99
Coyne, Alyssa N; Siddegowda, Bhavani Bagevalu; Estes, Patricia S et al. (2014) Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J Neurosci 34:15962-74

Showing the most recent 10 out of 19 publications