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Project 9

Leorah Freeman, M.D., Ph.D.

Dell Medical School, The University of Texas at Austin

Project Overview

Neurologist Léorah Freeman is the director of the Multiple Sclerosis Imaging and Outcomes Research Laboratory at The University of Texas at Austin’s Dell Medical School. As a physician-scientist, Dr. Freeman received training in both patient care and scientific research. She earned her M.D. and Ph.D.
from Université Pierre et Marie Curie in Paris, France. She specializes in the care of people with MS and other neuroinflammatory conditions.

Background

The Kathleen C. Moore Research Fund for Hope was established at Dell Medical School in September 2022. The fund will support research and programming related to multiple sclerosis under the direction of Dr. Freeman, a physician-scientist on the front lines of improving care for people and families affected by MS.

The Study

Dr. Freeman’s innovative research spans initiatives to provide more equitable MS care, support healthy aging with MS, bring new technology and state-of-the-art MRI analysis to the bedside, and advance precision medicine in MS. Funds will accelerate and expand Dr. Freeman’s work to better care for people living with MS and enable her to gather preliminary data needed to qualify for large-scale federal funding.

What’s Next

Dr. Freeman and her team are currently recruiting a diverse cohort of patients to study the impact of demographic, social and disease-specific factors on MS outcomes among people from vulnerable communities. She is also identifying predictive biomarkers of disease progression and response to therapies in MS patients over age 50 to establish best practices for the management of MS in older adults. Finally, she is working with UT engineers to develop a process to make MRI imaging — the gold standard in imaging for MS — more valuable, comfortable, and useful for patients and clinicians.

Project Overview

Neurologist Léorah Freeman is the director of the Multiple Sclerosis Imaging and Outcomes Research Laboratory at The University of Texas at Austin’s Dell Medical School. As a physician-scientist, Dr. Freeman received training in both patient care and scientific research. She earned her M.D. and Ph.D.
from Université Pierre et Marie Curie in Paris, France. She specializes in the care of people with MS and other neuroinflammatory conditions.

Background

The Kathleen C. Moore Research Fund for Hope was established at Dell Medical School in September 2022. The fund will support research and programming related to multiple sclerosis under the direction of Dr. Freeman, a physician-scientist on the front lines of improving care for people and families affected by MS.

The Study

Dr. Freeman’s innovative research spans initiatives to provide more equitable MS care, support healthy aging with MS, bring new technology and state-of-the-art MRI analysis to the bedside, and advance precision medicine in MS. Funds will accelerate and expand Dr. Freeman’s work to better care for people living with MS and enable her to gather preliminary data needed to qualify for large-scale federal funding.

What’s Next

Dr. Freeman and her team are currently recruiting a diverse cohort of patients to study the impact of demographic, social and disease-specific factors on MS outcomes among people from vulnerable communities. She is also identifying predictive biomarkers of disease progression and response to therapies in MS patients over age 50 to establish best practices for the management of MS in older adults. Finally, she is working with UT engineers to develop a process to make MRI imaging — the gold standard in imaging for MS — more valuable, comfortable, and useful for patients and clinicians.

Project 8

Kenneth Smith, Ph.D.

University College London, United Kingdom

Term: 7/1/21 – 6/30/22

Project Overview

 

The gradual accumulation of disability during progressive MS is mainly due to the loss of nerve cells (neurons) in the brain and spinal cord, but why they die is not known. One question is whether the neurons that die later in life do so because of damaging events happening at that time, or as the aftermath of earlier injury. This question is important because protecting neurons from ongoing inflammation is likely to require a different approach than protecting neurons that have survived this event, and now need repairing. The team is approaching this question with a rodent model using a new technique that allows the simultaneous detection of thousands of instructions from the cell’s control center (nuclei) that reveal pathways of damage. The team has already found that preventing an oxygen shortage that occurs within inflamed MS lesions may protect from slow degeneration. They will protect half of the rodents using this therapy, and compare the changes in injured cells in untreated rodents whose neurons are destined to slowly die, with changes in cells that have experienced the same inflammation, but survive. This will reveal specific mechanisms that determine cell death or survival, without confusing them with changes due to inflammation itself.

Potential Impact

 

This research is expected to provide clues to the development of therapies to prevent nerve degeneration in people with secondary progressive MS. This expert team plans to build on the new understanding to test the efficacy of potential therapies based on the new findings.

Project Overview

 

The gradual accumulation of disability during progressive MS is mainly due to the loss of nerve cells (neurons) in the brain and spinal cord, but why they die is not known. One question is whether the neurons that die later in life do so because of damaging events happening at that time, or as the aftermath of earlier injury. This question is important because protecting neurons from ongoing inflammation is likely to require a different approach than protecting neurons that have survived this event, and now need repairing. The team is approaching this question with a rodent model using a new technique that allows the simultaneous detection of thousands of instructions from the cell’s control center (nuclei) that reveal pathways of damage. The team has already found that preventing an oxygen shortage that occurs within inflamed MS lesions may protect from slow degeneration. They will protect half of the rodents using this therapy, and compare the changes in injured cells in untreated rodents whose neurons are destined to slowly die, with changes in cells that have experienced the same inflammation, but survive. This will reveal specific mechanisms that determine cell death or survival, without confusing them with changes due to inflammation itself.

Potential Impact

 

This research is expected to provide clues to the development of therapies to prevent nerve degeneration in people with secondary progressive MS. This expert team plans to build on the new understanding to test the efficacy of potential therapies based on the new findings.

Project 7

Carles Vilarino-Guell 

University of British Columbia 

Term: 3/1/2018 – 2/28/2019

Project Overview

Through the study of families with several family members diagnosed with MS, this team has recently identified a mutation in a gene called NR1H3 (also known as LXRA) which is associated with progressive MS. They have now created a mouse model with this mutation to be able to study the biological mechanisms responsible for the onset of MS. Now they are studying this model further, to explore the biological processes altered by this mutation, and observe any deficiencies in mobility and memory. The knowledge gained in this study may help to effectively stop the progression of MS.

Project Overview

Through the study of families with several family members diagnosed with MS, this team has recently identified a mutation in a gene called NR1H3 (also known as LXRA) which is associated with progressive MS. They have now created a mouse model with this mutation to be able to study the biological mechanisms responsible for the onset of MS. Now they are studying this model further, to explore the biological processes altered by this mutation, and observe any deficiencies in mobility and memory. The knowledge gained in this study may help to effectively stop the progression of MS.

Project 6

Akiko Nishiyama, MD, PhD 

University of Connecticut, Storrs Mansfield, CT

Term: 3/1/2019 – 2/29/2020 

Project Overview

Individuals with MS experience a progressive loss of the myelin that surrounds nerve fibers, which causes deterioration of the transmission of nerve signals. In chronic cases of MS, myelin sheaths are not efficiently repaired. Recent studies have shown that signals from nerve cells can activate immature myelin-making cells to mature and make myelin sheaths. The goal of the project is to explore whether oligodendrocyte precursor cells secrete molecules that are important for the formation of myelin and maintenance of nerve cell health. The team is addressing this by using a model in which immature myelin-making cells are inhibited from secreting molecules, and they are using specific fluorescent dyes to visualize the processes involved. The findings from these studies could be exploited to develop new therapies to enhance myelin repair or prevent neurodegeneration in MS.

Project Overview

Individuals with MS experience a progressive loss of the myelin that surrounds nerve fibers, which causes deterioration of the transmission of nerve signals. In chronic cases of MS, myelin sheaths are not efficiently repaired. Recent studies have shown that signals from nerve cells can activate immature myelin-making cells to mature and make myelin sheaths. The goal of the project is to explore whether oligodendrocyte precursor cells secrete molecules that are important for the formation of myelin and maintenance of nerve cell health. The team is addressing this by using a model in which immature myelin-making cells are inhibited from secreting molecules, and they are using specific fluorescent dyes to visualize the processes involved. The findings from these studies could be exploited to develop new therapies to enhance myelin repair or prevent neurodegeneration in MS.

Project 5

Dr. Ariele Greenfield, MD

Postdoctoral Fellowship Grant

Title: “Antigen Targets of CNS-Infiltrating B Cells in Early, Untreated Multiple Sclerosis” 

Term: 7/1/2016-6/30/2019 

Ariele Greenfield, MD is a postdoctoral fellow at the University of California, San Francisco. She received her MD at the University of California, San Diego and recently completed her residency in Neurology at UCSF where she served as chief of education. At UCSD, under the instruction of Dr. Laura Dugan, she studied the effects of interleukin-6 on motor learning in the aged with an NIH predoctoral training award. Her goals are to perform both translational neuroimmunology research and state-of-the-art patient care.

Background

In MS, immune cells attack components of the brain and spinal cord, leading to various symptoms and disability. No methods exist to prevent MS, because the earliest events that cause these immune cell attacks remain unknown. Certain subtypes of the immune cell group called B cells are found in the spinal fluid (the fluid that bathes the brain and spinal cord) in people with early MS; these are not found in people without MS, people with MS who are in remission, or those with later stages of MS. This timing suggests that these B cells may play a role in triggering MS.

Background

In MS, immune cells attack components of the brain and spinal cord, leading to various symptoms and disability. No methods exist to prevent MS, because the earliest events that cause these immune cell attacks remain unknown. Certain subtypes of the immune cell group called B cells are found in the spinal fluid (the fluid that bathes the brain and spinal cord) in people with early MS; these are not found in people without MS, people with MS who are in remission, or those with later stages of MS. This timing suggests that these B cells may play a role in triggering MS.

The Study

Dr. Greenfield and her team are obtaining blood and spinal fluid samples from people without MS and people with their first attack of MS. They are then isolating the B cells from these samples. Each B cell recognizes a specific set of targets, which can direct the B cell’s actions toward a certain tissue. They believe that the B cells are targeting myelin, the fatty substance that surrounds and protects nerve cells. However, the components of myelin targeted by these B cells are not yet known. Dr. Greenfield and her team are determining the individual targets of each B cell to understand what these cells may initially attack.

The Study

Dr. Greenfield and her team are obtaining blood and spinal fluid samples from people without MS and people with their first attack of MS. They are then isolating the B cells from these samples. Each B cell recognizes a specific set of targets, which can direct the B cell’s actions toward a certain tissue. They believe that the B cells are targeting myelin, the fatty substance that surrounds and protects nerve cells. However, the components of myelin targeted by these B cells are not yet known. Dr. Greenfield and her team are determining the individual targets of each B cell to understand what these cells may initially attack.

What’s Next

Therapies designed to block the interaction between B cells and their specific target may be useful for preventing or stopping MS.

What’s Next

Therapies designed to block the interaction between B cells and their specific target may be useful for preventing or stopping MS.

Project 4

Joo Woo Kim, PHD

Postdoctoral Fellowship Grant 

Icahn School of Medicine at Mount Sinai, New York, New York

Title: “Assessing Microstructural Integrity of Cervical Spinal Cord Gray and White Matter with Ultra-High Field Diffusion MRI for Progressive MS”

Term:  7/1/17-6/30/20

Joo-Won Kim, PhD, is a post-doctoral fellow at the Icahn School of Medicine at Mount Sinai in New York City. Dr. Kim received his PhD in applied mathematics and statistics from Stony Brook University. In 2016, he competed for and received a travel award to attend the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Kim’s postdoctoral training is focused on assessing damage to the spinal cord in people with MS using advanced imaging techniques.

Background

Gray matter (the tissue in the brain that contains mainly nerve cells and appears gray) and white matter (the tissue in the brain that contains mainly nerve fibers covered in myelin and appears white) in both the brain and spinal cord are damaged in MS. MRI (magnetic resonance imaging) scans of the brain is a standard way for physicians to track an individual’s disease activity. However, the spinal cord is fairly small, and imaging it is difficult with conventional imaging methods.

Background

Gray matter (the tissue in the brain that contains mainly nerve cells and appears gray) and white matter (the tissue in the brain that contains mainly nerve fibers covered in myelin and appears white) in both the brain and spinal cord are damaged in MS. MRI (magnetic resonance imaging) scans of the brain is a standard way for physicians to track an individual’s disease activity. However, the spinal cord is fairly small, and imaging it is difficult with conventional imaging methods.

The Study

Dr. Kim, along with his mentors, Dr. Xu and Dr. Matilde Inglese, are using an advanced type of imaging called ultra-high field diffusion MRI to scan gray and white matter tissue integrity of the spinal cord. The team is comparing MRI measurements in people with progressive MS compared to people without MS. They are also comparing people with MS who have different levels of disease severity. These non-invasive imaging methods will allow more precise monitoring of damage to the spinal cord in people with progressive MS.

The Study

Dr. Kim, along with his mentors, Dr. Xu and Dr. Matilde Inglese, are using an advanced type of imaging called ultra-high field diffusion MRI to scan gray and white matter tissue integrity of the spinal cord. The team is comparing MRI measurements in people with progressive MS compared to people without MS. They are also comparing people with MS who have different levels of disease severity. These non-invasive imaging methods will allow more precise monitoring of damage to the spinal cord in people with progressive MS.

What’s Next

Figuring out a good way to image MS damage in the spinal cord would open up the ability to use spinal cord imaging in larger studies and clinical trials, and allow more accurate assessment of damage to test therapies designed to treat MS.

What’s Next

Figuring out a good way to image MS damage in the spinal cord would open up the ability to use spinal cord imaging in larger studies and clinical trials, and allow more accurate assessment of damage to test therapies designed to treat MS.

Project 3

Anne-Katrin Probstel, MD, PhD 

Postdoctoral Fellowship Grant

University of California, San Francisco

Term:  7/1/18-6/30/21

Anne-Katrin Pröbstel earned her MD from Ludwig-Maximilians-University (Munich, Germany) and pursued a neurology residency at University Hospital Basel (Switzerland), during which she treated patients with MS. Dr. Pröbstel has received scholarships to study abroad and travel awards and is a recipient of the American Academy of Neurology International Scholarship Award.

Background

Types of immune cells called B cells play an important role in MS. There is growing awareness that the bacteria in the gut of people with MS are different from bacteria in people without MS, and that harmful bacteria found in the gut of people with MS may have detrimental effects on MS disease activity and possibly on B cell function.

Background

Types of immune cells called B cells play an important role in MS. There is growing awareness that the bacteria in the gut of people with MS are different from bacteria in people without MS, and that harmful bacteria found in the gut of people with MS may have detrimental effects on MS disease activity and possibly on B cell function.

The Study

Dr. Pröbstel and her team are investigating the role of gut bacteria in MS on B cells and inflammation. They are working to identify the gut bacteria in people with MS that may be harmful. They are transferring these harmful bacteria to mice to see if they make the MS-like disease called EAE worse. They are also testing whether eliminating these harmful bacteria improves EAE. Finally, they are determining whether these harmful bacteria are present in the blood or spinal fluid in people with MS.

The Study

Dr. Pröbstel and her team are investigating the role of gut bacteria in MS on B cells and inflammation. They are working to identify the gut bacteria in people with MS that may be harmful. They are transferring these harmful bacteria to mice to see if they make the MS-like disease called EAE worse. They are also testing whether eliminating these harmful bacteria improves EAE. Finally, they are determining whether these harmful bacteria are present in the blood or spinal fluid in people with MS.

What’s Next

Exploring the impacts of gut bacteria on MS disease initiation and activity may inform the development of probiotic strategies to treat people with MS.

What’s Next

Exploring the impacts of gut bacteria on MS disease initiation and activity may inform the development of probiotic strategies to treat people with MS.

Project 2

UCI Health MS Research Project

Funding by the Kathleen C. Moore Foundation

The Kathleen C. Moore Foundation’s generous support totaling $460,000 over six years (2017-2023), has enabled the UCI Health MS Program to initiate a clinical research project to study cognitive function testing and brain atrophy imaging by MRI for assessing disease activity and progression in Multiple Sclerosis. To establish the MS research program in Phase 1 (2017-19), UCI Health-Neurology recruited and hired one of the world’s foremost clinical MS diagnostics experts and translational neuro-immunologists, Dr. Alexander U. Brandt, from Charité – Universitätsmedizin, Berlin, Germany. A renewal grant in Phase 2 (2020-23), will support Postdoctoral Fellows to assist Dr. Brandt in on-going imaging, mapping, analysis, and publishing.

Detailed Impact of Funds

In Phase 1 (2017-19), we achieved the following:

• Established a high-quality clinical imaging assessment protocol to benefit clinical services by raising overall quality and utilizing up-to-date procedures. All UCI MS Center patients are now imaged with the state-of-the-art 3 Tesla fMRI scanner.

• Implemented a platform for quantitative image analysis, as well as quality-of-life assessments, e.g. fatigue, depression, etc.

• Developed a groundbreaking AI-based lesion segmentation system and web-based information system, which automatically generates image analysis data in real-time for treating MS physicians during clinical care visits.

• Installed state-of-the-art Optical Coherence Tomography (OCT) machine to assess patients’ retina for retrograde neurodegeneration and inflammation, an increasingly important biomarker for research and care in MS and related disorders.

In Phase 2 (2020-23):
• Principle Investigator Dr. Brandt will recruit internationally for up to two highly-qualified Post-doctoral Fellows to assist in the quantitative mapping, microstructural analyses and reporting/publishing results related to the association of qMRI measures with clinical disability and other MS biomarkers including neurodegeneration, demyelination and inflammation.

Detailed Impact of Funds

In Phase 1 (2017-19), we achieved the following:

• Established a high-quality clinical imaging assessment protocol to benefit clinical services by raising overall quality and utilizing up-to-date procedures. All UCI MS Center patients are now imaged with the state-of-the-art 3 Tesla fMRI scanner.

• Implemented a platform for quantitative image analysis, as well as quality-of-life assessments, e.g. fatigue, depression, etc.

• Developed a groundbreaking AI-based lesion segmentation system and web-based information system, which automatically generates image analysis data in real-time for treating MS physicians during clinical care visits.

In Phase 2 (2020-23):
• Principle Investigator Dr. Brandt will recruit internationally for up to two highly-qualified Post-doctoral Fellows to assist in the quantitative mapping, microstructural analyses and reporting/publishing results related to the association of qMRI measures with clinical disability and other MS biomarkers including neurodegeneration, demyelination and inflammation.

Project 1

Kirsten Evonuk Phd

Postdoctorate Fellowship Gift – Clevland, Ohio

Term: 7/1/19 – 6/30/22

Kirsten Evonuk, PhD. is a postdoctoral fellow at the Cleveland Clinic (Cleveland, Ohio). She received her PhD in neuroscience from the University of Alabama at Birmingham. Dr. Evonuk was awarded an educational travel grant and invited to give a platform presentation at the 2018 American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) conference, for which she was awarded Best Young Investigator Oral Presentation. She also presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2018.

Background

In MS, myosin, the fatty substance that surrounds and protects nerve fibers in the spinal cord and brain, is damaged, leading to symptoms in people with the disease. Glutamate, a chemical in the brain that is important for brain cell communication, is elevated in regions of the brain where MS lesions are located.

Background

In MS, myosin, the fatty substance that surrounds and protects nerve fibers in the spinal cord and brain, is damaged, leading to symptoms in people with the disease. Glutamate, a chemical in the brain that is important for brain cell communication, is elevated in regions of the brain where MS lesions are located.

The Study

Dr. Evonuk and her team are investigating the toxic effects of too much glutamate and whether excess glutamate interferes with myosin repair. They are using mice that lack glutamate docking sites (receptors that bind glutamate and transmit its effects) in the cells that make myosin. The mice have the MS-like disease EAE, and the researchers are asking if recovery from EAE and myosin repair are better in mice without glutamate receptors compared to normal mice.

The Study

Dr. Evonuk and her team are investigating the toxic effects of too much glutamate and whether excess glutamate interferes with myosin repair. They are using mice that lack glutamate docking sites (receptors that bind glutamate and transmit its effects) in the cells that make myosin. The mice have the MS-like disease EAE, and the researchers are asking if recovery from EAE and myosin repair are better in mice without glutamate receptors compared to normal mice.

What’s Next

The study will help determine whether a strategy of decreasing glutamate in cells that make myosin repair in MS.

What’s Next

The study will help determine whether a strategy of decreasing glutamate in cells that make myosin repair in MS.

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