Mapping the ALS Exposome to Gain New Insights Into Disease Risk and Pathogenesis

Dr. Eva Feldman and Dr. Stuart Batterman were jointly awarded a National Institutes of Health (NIH) grant (R01ES030049) on January 2020 to fund research into the effect of the environment on amyotrophic lateral sclerosis (ALS).  The goal is to collect data which will offer a foundation to uncover key pathways and mechanisms linked to exposure-induced changes that may identify biomarkers and therapeutic targets in ALS.

The environment contains toxic substances, such as persistent organic pollutants, pesticides, and heavy metals, that can injure nerves and cause neurological diseases. This grant begins to pinpoint which toxic environmental exposures increase the risk of developing ALS. The mechanism of toxic exposure-induced neurological injury can shed light onto pathological mechanisms in ALS, and identify possible therapeutic targets.

Metabolomic Signatures Linking ALS to Persistent Organic Pollutant Exposures

Dr. Eva Feldman was awarded a CDC grant (R01TS000289) to examine how persistent organic pollutants affect the metabolism of ALS patients. The research will seek to identify differences in metabolites with low versus high persistent organic pollutant exposure to determine metabolomic signatures associated with these environmental exposures.  These findings could provide insight into ALS disease mechanisms and could serve as a “signature” that an individual has been exposed to POPs and could develop ALS.

The Role of NK Cells in ALS

Dr. Feldman received funding from NIH grant R21NS102960 to investigate the role of the immune system in amyotrophic lateral sclerosis (ALS).  The primary goal is to demonstrate that innate lymphoid cells, especially NK cells, play a critical role in driving late stage ALS, and are a therapeutic target for disease treatment.

There is evidence that the immune system is involved in ALS progression; however, it is not known specifically which immune cells are involved and if they correlate with patient survival. Identifying specific immune cells that correlate with ALS development could identify possible treatment approaches.

Identifying NK Cells as Therapeutic Targets in ALS

Dr. Benjamin Murdock was awarded this grant by the Amyotrophic Lateral Sclerosis (ALS) Association (20-IIA-431[MGS1] ) to study the involvement of the immune system in ALS. The primary goal is to identify specific windows of disease when drug treatment will be the most effective, as well as to show direct evidence that NK cells directly kill motor neurons in ALS. Success of the study will allow us to transition immediately to pre-clinical and clinical trials with drug therapies. Dr. Murdock discovered that a subset of immune cells, called natural killer (NK) cells, are higher than normal in ALS patients and attack motor neurons. The grant will investigate the change in NK cell levels in ALS patients compared to healthy individuals over time. Since it is possible to block the activity of NK cells with drugs, this grant could lead to a new treatment approach in ALS.


Impact of Geospatial Factors and Environmental Pollutants of Amyotrophic Lateral Sclerosis in the State of Michigan

Dr. Stephen Goutman received a grant from the National Institutes of Health (K23ES027221) to investigate how environmental pollutants called persist organic pollutants (POPs), affect the severity of disease in amyotrophic lateral sclerosis (ALS) patients. The end goal of this project are to identify the location-based risk factors of ALS in Michigan. He will also determine if ALS clusters, i.e., an unusually high prevalence of ALS cases within a geographic area, correlate with the nearby presence of environmental toxins in the form of POPs.

ALS Gene and Environment Interactions

Together, Drs. Goutman and Bakulski were awarded a grant from the Amyotrophic Lateral Sclerosis (ALS) Association (20-IIA-532). This grant will examine ALS patients’ genetic profile to determine if there are mutations that predispose individuals to ALS through an interaction with environmental pollutants. It will also determine whether genetic mutations to bodily enzymes that breakdown pollutants may also be linked to ALS risk and progression.

Role of NADPH Oxidase 5 (NOX5) in Diabetic Neuropathy

Dr. Eva Feldman was awarded an NIH grant (U24DK115255) as part of DiaComp to study oxidative stress in neuropathy. The goal is to gain a better understanding of NOX5-derived free radicals to support our efforts to develop and validate novel therapies that prevent nerve damage in diabetes, prediabetes, and obesity.

Prediabetic, diabetic, and obese  individuals frequently develop neuropathy, i.e., nerve damage, but the mechanisms are not fully understood. Moreover, there are no treatments available to prevent or slow the progression of neuropathy. Oxidative stress, the presence of damaging “free radicals”, is one potential route of nerve damage. This grant will examine the contribution of an enzyme called NOX5 to free radicals in neuropathy, which could serve as a potential drug target.

Linking Nerve Bioenergetics with Metabolomics: New Insights into Diabetic Neuropathy

Dr. Eva Feldman received this NIH grant (R21NS102924) to investigate the link between energy production and neuropathy in prediabetes and diabetes . The major goal of this project is to identify bioenergetics—how cells transform energy—pathways whose regulation play crucial roles in the pathogenesis of diabetic peripheral neuropathy.

Mitochondria are cellular structures that generate the energy needed for keep cells and organisms alive and may be defective during the development of neuropathy. This study will study how mitochondria fail in neuropathy and also if this is linked to the presence or absence of certain metabolites.

Michigan Mouse Metabolic Phenotyping Center

Dr. Feldman’s research uses mouse models of diabetes to understand the mechanisms that lead to neuropathy. This NIH grant (U2CDK110768) was awarded to measure prediabetes- and diabetes-induced nerve, eye, and kidney damage in mice. The ultimate goal of this project is to phenotype murine models for neuropathy.

Integrated Systems Biology Approach to Diabetic Microvascular Complications

Dr. Eva Feldman was awarded this NIH grant (R24DK082841) to investigate microvascular complications in diabetes.

Microvascular complications refer to the gradual damage to nerve, eye, and kidney tissues during diabetes. Controlling blood glucose does not always prevent these from occurring, so Dr. Feldman and her team are investigating the effect of abnormal lipid (fats) profiles. They will look at tissue-specific effects of lipids in nerve, eye, and kidney and will will seek to identify lipid “signatures”, i.e., the presence or absence of specific lipids, that are linked to tissue-specific complications. It will also seek to identify potential lipids that could be possible treatment targets.

Targeting Inflammation and Salsalate as a Novel Therapy for Diabetic Neuropathy

Dr. Eva Feldman jointly received this NIH grant with Dr. Rodica Pop-Busui (R01DK107956) to run a clinical trial in type 1 diabetes patients. They are testing the effectiveness of a compound called salsalate on the progression of neuropathy.

SEARCH for Diabetes in Youth Cohort Study

Dr. Eva Feldman was awarded this CDC & NIH grant (R01DK108173) as a member of a larger study called “SEARCH for Diabetes in Youth Cohort Study”. This clinical study is being performed to assess the occurrence of neuropathy in young individuals with type 1 and type 2 diabetes  to monitor the onset of diabetic autonomic and peripheral neuropathy in children.

The International Diabetic Neuropathy Consortium (IDNC)

This grant was awarded by the Novo Nordisk Foundation to Dr. Eva Feldman. The study will look at the presence and absence of certain metabolites in the blood of both mouse models and humans with type 2 diabetes. The goal is to search for specific patterns of metabolites, or “signature”, of diabetes and to identify targets to develop treatments.

The Effect of High Intensity Interval Training and Surgical Weight Loss on Distal Symmetric Polyneuropathy Outcomes

Dr. Callaghan won this grant from the National Institutes of Health (R01DK115687) to evaluate approaches for preventing diabetic neuropathy. The study will test two approaches. First, participants will be divided into two groups, one that undergoes bariatric surgery (weight-loss surgery) and one that does not. Second, participants from each group (surgery and no surgery) will be divided randomly into high intensity exercise or regular exercise. Patients will be evaluated for neuropathy to determine the most effective approach(es). This study is registered at (NCT03617185).

Sphingolipid and Fatty Acid Biology in Prediabetes and Neuropathy

Dr. Rumora was awarded a grant from the National Institutes of Health (K99DK119366) to investigate a dietary method for preventing diabetes induced neuropathy. The goal is to identify monosaturated fat (MUFA) supplementation as an accessible and targeted therapy to reverse toxic ceramide accumulation and reverse or halt the progression of neuropathy. In this study, Dr. Rumora will determine whether a diet enriched in monounsaturated fatty acids, such as present in olive oil and other oils, instead of saturated fatty acids, such as found in butter, can prevent the development or severity diabetic neuropathy. She will also be investigating the link of a type of lipid called ceramides with diabetic neuropathy.

Neural Stem Cell Transplantation: A Novel Cellular Therapy for Alzheimer's Disease

This NIH grant was jointly awarded to Dr. Eva Feldman and Dr. Geoffrey Murphy (U01AG057562) to evaluate the safety and effectiveness of injecting stem cells into mouse models of Alzheimer’s disease. The major goals of this project are to determine the therapeutic impact of neural stem cell transplantation in Alzheimer’s disease mouse models and establish safety and feasibility in non-human primates.

Training in Clinical and Basic Neuroscience

Dr. Eva Feldman is dedicated to training the next generation of medical doctors, researchers, and physician scientists. In her role as mentor, Dr. Feldman was awarded an NIH training grant (DT32NS007222) to advance the medical and research education of junior members of her laboratory. This project will train M.D. and Ph.D. fellows in clinical and basic neuroscience.

Dr. Eva Feldman is dedicated to training the next generation of medical doctors, researchers, and physician scientists. In her role as mentor, Dr. Feldman was awarded an NIH training grant (DT32NS007222) to advance the medical and research education of junior members of her laboratory. This project will train M.D. and Ph.D. fellows in clinical and basic neuroscience.