Project Details
Description
ABSTRACT
Progressive supranuclear palsy (PSP) is a devastating atypical parkinsonian disorder that currently lacks
meaningful symptomatic therapies, reduces lifespan and greatly impairs daily function and quality of life. It is
often difficult to distinguish from Parkinson disease (PD) clinically, which is crucial for appropriate and timely
management, prognosis and clinical trial enrollment. Despite a critical need for a reliable diagnostic marker for
parkinsonian disorders, there is currently no biomarker that can be used in routine clinical practice to
distinguish between PSP and PD. The purpose of this project is to discover cerebrospinal fluid (CSF)
biomarkers that reliably distinguish between PSP, PD and healthy individuals. The difficulty of identifying
reliable biomarkers can be attributed to the variability of clinical samples, low abundance of proteins that are
involved in the pathogenesis of PSP and PD, and the lack of reproducibility in validating biomarker candidates.
To overcome these limitations, we propose use of a large CSF cohort with greater statistical power for true
discovery, and deep proteome analysis to reveal PSP biomarkers that are involved in PSP pathogenesis, but
are present at low abundance. In addition, multiplexed sample analysis by isobaric tandem mass tagging
(TMT) with a common reference for data normalization will ensure robust analytical precision of quantitative
proteomic data for discovery from a larger set of samples. Moreover, additional proteomic analysis of brain
tissue will be used to select those biomarkers that show differential expression in CSF as well as the globus
pallidus, a representative brain region used to pathologically define PSP. These discovery platforms will utilize
a bioinformatics approach to select the most plausible candidates for targeted validation studies followed by an
intensive validation of the discovered biomarker candidates. To achieve these goals, we propose four aims:
Specific Aim 1: To prospectively collect CSF on patients with clinically well-characterized PSP. Specific Aim
2: To discover proteins that are differentially expressed in patients with PSP compared to controls and PD. We
plan to carry out a quantitative proteomic analysis of CSF and globus pallidus samples from patients with PSP,
PD and from controls by employing TMT-based multiplexing technology. With this approach, we expect to
obtain a more comprehensive coverage of a larger number of proteins quantified across the analyzed samples.
Specific Aim 3: To prioritize PSP biomarker candidates based on an integrative analysis of alterations in CSF
and globus pallidus. By integrating the expression changes in CSF and brain tissue with a network approach
that takes advantage of the known biological pathways that have been described in PSP, our proposal will be
able to select reliable PSP biomarker candidates for validation by targeted PRM experiments. Specific Aim 4:
To validate candidate protein biomarkers in a larger cohort using targeted parallel reaction monitoring (PRM)
mass spectrometry using CSF samples from a PSP cohort at Johns Hopkins University, the University of
Pennsylvania, UCSF and PDBP. Biomarkers that are selected by algorithms based on these PRM experiments
will finally be confirmed using blinded PDBP CSF samples from PSP and will be compared to CSF samples
from PD. Through the approaches outlined above, we expect to discover and validate reliable PSP biomarkers
that are distinguishable from PD in a reproducible manner.
Status | Finished |
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Effective start/end date | 8/1/18 → 4/30/23 |
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