Project Details
Description
PROJECT SUMMARY/ABSTRACT: PROJECT 3
A major hurdle to identifying disease mechanisms in amyotrophic lateral sclerosis (ALS) is the heterogeneous
nature of the disease. People with ALS exhibit a wide variety of clinical presentations, rates of progression and
underlying genetic risk factors. ALS is more likely a syndrome rather than a single disease that leads to a
recognizable clinical phenotype that we call ALS. Our approach to unraveling the pathophysiology of ALS is to
focus on a specific genetically-defined population where the disease is defined by a common underlying
mechanism. Here, people carrying the C9orf72 G4C2 hexanucleotide repeat expansion mutation (c9ALS) are
the genetically defined population. As opposed to sporadic ALS (sALS), where an array of genetic,
environmental, and unknown factors drive disease, a common disease-causing pathophysiology underlies
c9ALS. The proposition is that investigating this relatively homogenous ALS genetic subgroup will provide a
window of opportunity for understanding disease mechanisms and developing treatments. The hope is that
discoveries in this smaller group of patients will be applicable to the larger ALS population. In this project, we
will use next generation mass spectroscopy and systems biology analysis to discover biomarkers of disease
pathways and progression. In Specific Aim 1, we will interrogate human motor cortex from c9ALS and sALS
patients to generate proteomic networks and modules that define c9ALS. In Specific Aim 2, we will partner
with the investigators of Project 1 to define proteomic networks in a C9orf72 G4C2 mouse model; this will allow
us to analyze proteomic changes in brain at several time points during disease progression. In addition,
proteomic analysis of brains from mice treated with an antisense oligonucleotide (ASO) targeting G4C2
transcripts will allow for the identification of protein signatures associated with a disease-modifying drug. In
Specific Aim 3, proteomic signatures common to both human and mouse disease will be targeted in CSF
samples from c9ALS patients and asymptomatic C9orf72 expansion carriers, both in cross sectional and
longitudinal analyses. The ultimate goal of this project is the discovery of novel biomarkers of disease
pathways and progression that will be important for ongoing research into disease pathogenesis and also for
future clinical trials.
Status | Finished |
---|---|
Effective start/end date | 4/1/20 → 3/31/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $432,289.00
- National Institute of Neurological Disorders and Stroke: $416,660.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.