Researchers identify proteins that could predict liver transplant
rejection
Finding could help physicians catch rejection earlier and modify immunosuppression

Date:
January 27, 2022
Source:
Northwestern University
Summary:
Scientist have discovered families of proteins in the body that
could potentially predict which patients may reject a new organ
transplant, helping inform decisions about care.



FULL STORY ========================================================================== Northwestern University scientist have discovered families of proteins
in the body that could potentially predict which patients may reject a
new organ transplant, helping inform decisions about care.


==========================================================================
The advancement marks the beginning of a new era for more precise study
of proteins in specific cells.

Scientists tend to look at shifting patterns of proteins as if through
goggles underwater, taking in just a fraction of available information
about their unique structures. But in a new study to be published January
27 in the journal Science, scientists took a magnifying glass to these
same structures and created a clarified map of protein families. They
then held the map up in front of liver transplant recipients and found
new indicators in immune cell proteins that changed with rejection.

The result, the Blood Proteoform Atlas (BPA), outlines more than 56,000
exact protein molecules (called proteoforms) as they appear in 21
different cell types -- almost 10 times more of these structures than
appeared in similar previous studies.

Scratching the surface of potential "We're working to create the protein equivalent of the Human Genome Project," said Neil Kelleher, a leading
expert in proteomics and co-corresponding author of the paper. "The BPA
is a microcosm of that, including a specific-use case." Kelleher is the
Walter and Mary Glass Professor of Molecular Biosciences and professor
of chemistry in Northwestern's Weinberg College of Arts and Sciences
and a professor of medicine in Northwestern University Feinberg School
of Medicine. He is also the director of the Chemistry of Life Processes Institute (CLP) and faculty director of Northwestern Proteomics, a center
of excellence within CLP that develops novel platforms for drug discovery
and diagnostics.



==========================================================================
Each human gene has at least 15 to 20 unique forms of processed proteins (proteoforms). And with 20,300 individual genes in the human body, there
are millions of proteoforms created by genetic variation, modification
or splicing.

Kelleher said with a complete roadmap of each gene's family of proteins
-- the goal of a major science initiative known as the Human Proteoform
Project - - discoveries about disease, aging and new therapeutics will accelerate.

The Kelleher lab uses state-of-the-art mass spectrometry and data analysis
to identify proteofoms in cells and blood efficiently, keeping proteoforms intact in a form of "top-down" analysis rather than cutting them up into
tiny pieces as with the industry standard.

"We're starting to see the complexity," he said. "In this paper, we
demonstrate patient-, cell type- and proteoform-specific measurements,
which allows us to get to better biomarkers." A blood test for liver transplant rejection Having team members across disciplines allows the
project to conceptualize a move from lab bench to bedside. As Kelleher
probes the scientific basis for phenomena in the cell, co-corresponding
author and Northwestern Medicine transplant hepatologist Josh Levitsky
works with him to understand how these could be applied to a specific
system.



========================================================================== Levitsky, professor of medicine, surgery and medical education at
Feinberg, originally connected with Kelleher through his leadership in
the biomarkers space, in which measurable signs in the blood are used
to predict health metrics in patients facing disorders -- and in this
instance, liver transplant rejection.

"It was really important for Neil that there was a biologically relevant example to contextualize how these proteoform panels can identify diseases
non- invasively as markers," Levitsky said. "And there's also a need
in my field to have mechanistic biomarkers that are more relevant to
their immune biological pathways. This could be the start of a new era
in cell-specific markers." Physicians must suppress the immune system
with drug therapy and monitor liver transplant recipients for signs of rejection, often only responding after an episode has begun. Guesswork throughout this process could be eliminated with specific knowledge
about what's happening at the most granular level.

With the BPA as a reference map, the team took blood samples from
participants in one of Levitsky's biomarker collection studies. They
examined which proteoforms seemed to activate in response to the
transplant and identified those that changed compared to patients
without rejection.

Next, the Levitsky and Kelleher team developed a panel of 24 proteoforms
from the initial study and looked at them in transplant recipient samples
from across the country. They found the same proteoforms lit up as in
the first trial.

Moving the field forward "The promise here is to be able to use this
panel moving forward to be able to identify patients who have no signs
of rejection versus those who have very early evidence of rejection,"
Levitsky said. "If we can pick up on this several weeks before rejection actually happens, we might be able to modify immunosuppression."
Levitsky continues to examine how proteoforms change in transplant
recipients over time to develop additional biomarkers that may inform
how he treats patients down the line. Kelleher said as the number of
cell types in the atlas grows, so too will potential ways to use it. In addition to broadening understandings of human biology, the BPA could
have similar applications across immune disorders.

The study, "The Blood Proteoform Atlas: A reference map of proteoforms
in human hematopoietic cells," was conducted across six institutions
with 26 scientists.

Rafael D. Melani, a research assistant professor in the Kelleher Group,
was the first author of the paper, along with Vincent R. Gerbasi, also
from Northwestern, and Lissa C. Anderson from Florida State University.

The research was supported by the National Institute of General
Medical Sciences of the National Institutes of Health (award numbers:
P41 GM107569, R21LM013097, T32 GM105538 and R21 AI135827), the Human Biomolecular Atlas Program (award number: UH3 CA246635-02), Paul
G. Allen Frontiers Program Award (award number 11715), the Knut and Alice Wallenberg Foundation grant (2016.0204) and the Swedish Research Council
grant (2017-05327). Work performed at the National High Magnetic Field Laboratory is supported by the National Science Foundation Division of Materials Research and Division of Chemistry and the State of Florida.

========================================================================== Story Source: Materials provided by Northwestern_University. Original
written by Lila Reynolds. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Rafael D. Melani, Vincent R. Gerbasi, Lissa C. Anderson, Jacek
W. Sikora,
Timothy K. Toby, Josiah E. Hutton, David S. Butcher, Fernanda
Negra~o, Henrique S. Seckler, Kristina Srzentić, Luca Fornelli,
Jeannie M.

Camarillo, Richard D. LeDuc, Anthony J. Cesnik, Emma Lundberg,
Joseph B.

Greer, Ryan T. Fellers, Matthew T. Robey, Caroline J. DeHart,
Eleonora Forte, Christopher L. Hendrickson, Susan E. Abbatiello,
Paul M. Thomas, Andy I. Kokaji, Josh Levitsky, Neil L. Kelleher. The
Blood Proteoform Atlas: A reference map of proteoforms in human
hematopoietic cells.

Science, 2022; 375 (6579): 411 DOI: 10.1126/science.aaz5284 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220127141601.htm

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