USA: Cornell Center for Enervating NeuroImmune Disease and Maureen Hanson

Andy · Apr 11, 2023

Denise said: ↑

This $9.5 million grant (over 5 years) looks pretty much like a follow-on to the 2017 $9.4 million grant for the CRC.
This is just one of the NIH funded CRCs though. I wonder what the details are on the others and on the data center?
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Yep, it's a follow on from their original CRC grant.

Given that the NIH recently re-promoted their funding call for the CRCs, see https://www.s4me.info/threads/usa-nih-national-institutes-of-health-news.18724/page-9#post-468953, I'm guessing that, unless there are other announcements to be made soon, either Jackson Labs and Columbia University didn't apply for funding, or they weren't successful in their applications.

Andy · Apr 11, 2023

"We have placed a description of the projects to be carried out by our renewed NIH ME/CFS Center onto our website. More information about opportunities for subject participation will be provided later. https://neuroimmune.cornell.edu/research/"

https://twitter.com/user/status/1645876195399987200

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Hutan · Apr 11, 2023

The research priorities from the website
Muscle tissue

The goal is to identify molecular and cellular alterations present in ME/CFS skeletal muscles through innovative approaches to capture the transcriptome and epigenome with single-cell and spatial resolution in human biopsies. Using single nuclei isolated from muscle biopsies, the genes expressed in each cell, as well as the configuration of chromosomes in each cell, will be determined. Gene expression information will also be obtained from small regions of cross-sections (slices) of muscle tissue (spatial transcriptomics). All of this information will be used to determine whether specific types of muscle-resident cells are dysregulated at the transcriptional and epigenetic levels in ME/CFS subjects vs. controls.
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Immune Dsyregulation in Classical Monocytes and Platelets

The project is based on discoveries our Center made previously, in which we identified classical monocytes, a component of the innate immune system, as the circulating immune cells that show that strongest dysregulation in gene expression in ME/CFS. We also looked for changes in gene expression across the immune system that might correlate with post-exertional malaise (PEM), using samples collected before exercise and 24 hours later. This approach revealed that PEM after a strenuous exercise challenge results in a distinctive change in platelets. Thus, going forward, our major goals are to comprehensively investigate monocyte and platelet abnormalities in ME/CFS.

Two complementary approaches will be used to examine monocytes in ME/CFS. First, multiomic approaches will comprehensively determine the gene regulatory changes in monocytes that occur in ME/CFS. One possible result from these experiments will be the identification of the key drivers of monocyte dysregulation in ME/CFS. Second, assays will be performed to test whether the illness results in alterations in the ability of monocytes to migrate and differentiate into macrophages, a critical function of monocytes. These assays are motivated by our current data, which suggests that monocytes in ME/CFS are aberrantly primed to enter tissues, which is a normal function of monocytes but may be inappropriately active. The biopsy project led by Dr. Cosgrove will examine this possibility by directly investigating macrophages in muscle. We will be able to examine links between monocyte alterations in the circulation and the possible consequences in tissue.

Platelet defects could contribute to circulatory and other symptoms in ME/CFS. Our goal is to examine the platelet transcriptome comprehensively and also to perform assays to test platelet function. We will examine interactions between platelets and other immune cells in ME/CFS that might be contributing to their altered state in the illness. We will also be able to find out whether the cargo of platelet-derived extracellular vesicles is altered in ME/CFS, complementing the analysis of platelets
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I note the focus on classical monocytes - I think non-classical monocytes were looking interesting in someone's study but, it sounds as though the Cornell team are following a clue.

Cell-free RNA - before and after exercise

We will examine the cell-free RNA (cfRNA) molecules present in the circulation at all 4 time points when blood was collected in the first phase of our NIH Center (2017-2023). Plasma samples from 173 subjects who underwent the two-day exercise test have been banked for use.

91 ME/CFS patients and 82 age and gender-matched sedentary controls performed two successive CPETs, separated by 24 hours. Blood samples taken at four different time points, baseline (preDay1), 15 minutes post CPET1 (postDay1), after a 24 hour recovery period (preDay2), and 15 minutes post CPET2 (postDay2).

CfRNA is released from both solid tissues and immune cells as a result of cell death. One way to access the proportion of cell types that are turning over is to determine the source of cfRNA. The cellular source of cfRNA in each subject can be identified by comparing to the known levels of differential gene expression in different cell types. Our premise is that identification of the cell types of origin of cfRNA in ME/CFS patients and controls before and after exercise may give us clues to the disruptions that happen after ME/CFS individuals elevate their activity levels. In particular, learning which cell types have altered patterns of injury and cell death in ME/CFS may reveal immune and tissue involvement in the pathophysiology of Post-Exertional Malaise (PEM).
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Extracellular vesicle cargo - changes with exercise

Extracellular vesicles will be isolated from frozen blood samples collected from the muscle biopsy participants as well as from samples collected before and after exercise tests. Affinity purification methods will be used to obtain EVs that originated from platelets, brain, and endothelial cells. The protein cargo of these three types of tissue-specific EVs will then be characterized by Somascan analysis. The small RNA content of the EVs will be assessed by RNA sequencing. Statistical tests will be used to assess 1) the differences between ME/CFS and control protein and RNA cargo within each EV subpopulation, 2) the differences in protein and RNA cargo between EVs from different tissues. A key question is whether EVs from specific ME/CFS tissues vs control tissues differ in the protein pathways represented by the EV cargoes, thus indicating dysregulation of the function of those tissues.

We will analyze the protein data to determine how exercise affects the protein cargo of EVs and how the proteins and protein networks may differ between patients and controls. Utilizing samples at baseline and following induction of post-exertional malaise will help us learn how the protein content of EVs changes as a result of exercise and thus their possible involvement in the symptom. We will also be able to correlate findings from data collected from the muscle biopsy participants.
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Endothelial dysfunction

Increasing evidence implicates disturbances in hemostasis and endothelial function in ME/CFS. Assays for endothelial dysfunction can be performed by measurements of circulation by the EndoPat® as well as by examining endothelial cells in vitro and in vivo. Gene expression in endothelial cells in muscle biopsies from ME/CFS subjects and controls will be compared. A recent report indicated that cultured endothelial cells treated with plasma from ME/CFS subjects caused less nitric oxide (NO) production than when cells were treated with control plasma. We will attempt to repeat and extend these observations.
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Multiomics

We plan to integrate the analysis of datasets from different types of assays. We think this will yield additional insights into the pathophysiology of ME/CFS and in particular, point toward molecular mechanisms of PEM. Integrating our multi-omic data with the clinical and exercise physiology data of our patient cohort may allow us to identify unique molecular signatures in different subsets of ME/CFS patients. These molecular signatures may provide a basis for tailored diagnostics and treatments for clinical and demographic subsets of ME/CFS patients in the future.

Predictive modeling using a combination of molecules in different classes that have significantly different levels in ME/CFS patients and controls at baseline may enable more accurate classification of ME/CFS patients and healthy controls than could an assay utilizing biomarkers only from a single class.
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To me, it all looks sensible and promising, with some attempt at replication of results and a good focus on PEM by looking at what happens after exercise. Also, the studies have some synergy, and there is a plan to make the most of that. I think this group's work is a source of hope for us.

Hutan · Apr 12, 2023

Mij said: ↑

https://news.cornell.edu/stories/2023/04/95m-fund-cross-disciplinary-chronic-fatigue-research
$9.5M to fund chronic fatigue syndrome research
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Noting that this announcement of NIH funding of the Cornell team has been merged into this thread, in case you missed it

Sly Saint · Apr 12, 2023

Merged thread

A Cornell multidisciplinary research center that studies chronic fatigue syndrome has received a five-year, $9.5 million grant from the National Institutes of Health’s National Institute of Allergy and Infectious Disease – funding that will enable experts from disparate fields to work together on the mysterious and debilitating condition.

The Cornell Center for Enervating Neuroimmune Disease, established in 2017, ultimately seeks to understand the biological basis and develop a treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disorder for which there are currently no effective therapies.

ME/CFS affects an estimated 3 million people in the United States and some 65 million worldwide, causing some to be ill for decades and unable to work. The disease leads to overwhelming fatigue that rest does not alleviate. Symptoms may include brain fog, body pains, headaches, difficulty sleeping and prolonged increases in symptoms after mild physical exertion or exercise.

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Credit: Noël Heaney/Cornell University
From left, Andrew Grimson, associate professor in the Department of Molecular Biology and Genetics in the College of Arts & Sciences; Iwijn De Vlaminck, associate professor in the Cornell Meinig School of Biomedical Engineering; Maureen Hanson, Liberty Hyde Bailey Professor in CALS; Ben Cosgrove, associate professor in the Cornell Meinig School of Biomedical Engineering; Jen Grenier, director of the Genomics Innovation Hub in the Cornell Institute of Biotechnology; and Carl Franconi, administrative manager of the Center for Enervating Neuroimmune Disease.

“What is desperately needed in ME/CFS are effective treatments that not only improve certain symptoms, but actually ameliorate the whole disease, so that people can get their lives back,” said Maureen Hanson, Liberty Hyde Bailey Professor in the College of Agriculture and Life Sciences (CALS), who is the center’s director and co-principal investigator of the grant, which starts on April 1.

“When we started the Center in 2017, our goal was to take a broad interdisciplinary approach, with the hope that we would find specific molecular changes in ME/CFS; now that we have found these changes, we can target our research on these changes and understand their impact, ultimately moving towards a cure,” said Andrew Grimson, associate professor in the Department of Molecular Biology and Genetics in the College of Arts and Sciences, the center’s associate director and co-principal investigator on the grant.
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full article
https://news.cornell.edu/stories/2023/04/95m-fund-chronic-fatigue-syndrome-research

petrichor · Apr 12, 2023

Good to hear

Simone · Apr 15, 2023

Does anyone know what this means given that applications for the CRCs RFA aren’t open until next month? How did Hanson get this funding? What does that mean for the other CRCs?

Andy · Apr 17, 2023

Simone said: ↑

Does anyone know what this means given that applications for the CRCs RFA aren’t open until next month?
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I assume that the gap between announcement and the application period opening is to give time for an application to be put together by anybody interested in applying.

Simone said: ↑

How did Hanson get this funding?
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The CRC RFA from last year.

Simone said: ↑

What does that mean for the other CRCs?
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That either they didn't apply last year or were unsuccessful in their application.

Sly Saint · Oct 9, 2023

Friday October 20, 2023 UMass

Maureen Hanson is the Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics at Cornell University. Since her Ph.D. and postdoctoral studies at Harvard University, Dr. Hanson’s research has focused on the molecular, cellular, and biochemical aspects of plant chloroplast and mitochondria. Her current research encompasses both plant biology and biomedical research on the disease Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Among her many honors, Dr. Hanson is a fellow of the American Society for Plant Biology and the American Association for the Advancement of Science, as well as a member of the American Academy of Arts and Sciences and the National Academy of Sciences.

In this lecture, Dr. Hanson will discuss the disease Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Until the recent pandemic, the possibility that RNA viruses can persist and cause post-viral illnesses was largely ignored. In the mid-80s, there was a hidden pandemic of ME/CFS. Similarities and differences between these two disabling illnesses are still emerging.

In person event posted in Research for Faculty , Staff , and Current students
Related program areas

Biochemistry and Molecular Biology

Pre-Med/Pre-Health

Related departments

Biochemistry and Molecular Biology

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https://www.umass.edu/natural-sciences/events/enigma-post-viral-illnesses

Kitty · Oct 9, 2023

Sounds great, I hope we get to hear afterwards about what she said.

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