PNR&D reach expands through research collaborations

The impact of the Program for Neurology Research & Discovery is amplified by a wide range of collaborations with researchers across the University of Michigan, the United States and the world.

Working with researchers outside the PNR&D not only allows access to much larger patient cohorts worldwide, but allows PNR&D scientists studying amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and peripheral neuropathy to work across disciplines in an effort to gain a fuller, more integrated understanding of these diseases of the central and peripheral nervous systems.

Active collaborations include:

* In collaboration with Raymond Yung, MBChB, (U-M Department of Internal Medicine), we are applying a systems biology approach combining high-throughput profiling assays, qPCR, and pyrosequencing to determine whether miRNAs are altered in sporadic ALS.

* In collaboration with Sami Barmada, M.D., Ph.D. (U-M Department of Neurology) and Mats Ljungman, Ph.D. (U-M Department of Radiation Oncology, Comprehensive Cancer Center and Translational Oncology Program and the Department of Environmental Health Sciences, School of Public Health), we are identifying common and unique dysregulated mature miRNA changes in patient-derived fibroblasts from sporadic ALS and C9orf72 ALS subjects using NanoString technology.

* An additional collaborative project with Sami Barmada is also under way, and is focused on differentiating iPSC lines from ALS-patient and healthy control fibroblasts into neurons to assess differential miRNA expression, cell phenotype, and cell survival using Longitudinal Fluorescence Microscopy imaging technology.

* In collaboration with Sunitha Nagrath, Ph.D. (U-M Department of Chemical Engineering), we are determining the biological role and clinical relevance of circulating exosomes in ALS pathology by isolating and quantitating circulating and brain exosomes to characterize the molecular cargo from ALS and healthy control human samples.

* In collaboration with John Kao, M.D. (U-M Department of internal Medicine), we are correlating differences in microbiota diversity in the intestinal system of patients with the development of ALS.

* In collaboration with Tatiana Botero, D.D.S., M.S. (U-M Dental School), Manish Arora, B.D.S, M.P.H., Ph.D. (Mount Sinai Hospital, New York, Department of Preventative Medicine), and Stuart Batterman, Ph.D. (U-M School of Public Health), we are identifying aberrant concentrations and/or absorbance patterns of trace elements in permanent sALS teeth that could be associated with environmental/occupational exposures or nutritional factors leading to sALS.

* In collaboration with Stephen Goutman, M.D. (U-M Department of Neurology) and the Michigan Institute for Clinical & Health Research, we are identifying upregulated pro-inflammatory immune cell populations that correlate with ALS disease progression. The goal is to ultimately identify potential biomarkers or therapeutic targets of disease.

* In collaboration with Brad Foerster, M.D. (U-M Department of Neurology), we are using PET scans to assess macrophage activation levels in the CNS of ALS versus healthy and correlating these data with markers of inflammation in the peripheral blood.

* In collaboration with Nils Walter, Ph.D. (U-M Department of Chemistry), we are using high-resolution single-molecule fluorescence imaging to evaluate miRNA dysregulation and determine whether aberrant interactions between miRNAs and ALS-hallmark protein aggregates disrupt epigenetic homeostasis in the nervous system and lead to the progression of ALS.

* In collaboration with Ben Reubinoff, M.D., Ph.D. (Hadassah Medical Center, Israel), we are developing iPS cell lines from patients with familial and sporadic ALS to study pathogenic disease mechanisms and test therapies.

* In collaboration with Neuralstem Inc. (Germantown, MD), we are developing novel cellular therapies for ALS and AD based on Neuralstem’s human neural stem cell lines. Specific projects include identifying optimal stem cell lines for pre-clinical testing, and utilizing stem cells in rodent models to determine the efficacy of stem cell treatment. Additional projects include examining the effect of the drug NSI-189 on cognitive and biochemical changes in the brains of high fat-fed mice.

* In collaboration with Geoff Murphy, Ph.D. (U-M Molecular and Behavioral Neuroscience Institute), we are determining the impact of our NSC therapies on AD-related cognitive deficits of AD mice. Specific tasks include establishing a battery of well-characterized hippocampal-dependent behavior tasks that will enable the evaluation of clinically relevant measures of cognition such as learning and memory, providing important data required by the FDA for future clinical translation of our lead NSC candidates. Additional studies in collaboration with Dr. Murphy include using behavioral tests to examine the effects of high fat feeding and specific drugs on mouse cognition.

* In collaboration with Cindy Chestek, Ph.D. (U-M Department of Biomedical Engineering) and Parag Patil, M.D., Ph.D. (U-M Department of Neurosurgery), we are devising methods to optimize MRI-guided stereotactic stem cell transplantation techniques to the peri-hippocampal region of the brain. This will allow us to ensure the safety of our approach, enabling rapid translation to early phase trials in patients.

* In a collaboration with Peter Scott, Ph.D. (U-M Department of Radiology and Nuclear Medicine), we are testing several novel PET tracers in our AD mouse models to identify a longitudinal biomarker that can be easily translated to AD patients.

* In collaboration with Julia Raykin, Ph.D. (Georgia Institute of Technology), we have received high-throughput, customized, and target-specific quantitative image analysis techniques to measure AD related pathologies in tissue.

* In collaboration with Charles Burant, M.D., Ph.D. (U-M Department of Computational Medicine & Bioinformatics; The Michigan Regional Comprehensive Metabolomics Resource Core), Subramaniam Pennathur, M.B.B.S. (U-M Department of Internal Medicine; Nutrition Obesity Research Center Molecular Phenotyping Core), Frank Brosius III, M.D. (U-M Department of Internal Medicine and Molecular and Integrative Physiology), Matthias Kretzler, M.D. (U-M Department of Internal Medicine, Computational Medicine and Biology), and Thomas Gardner, M.D., M.S. (U-M Department of Ophthalmology and Visual Sciences), we are using the BKS db/db mouse model of type 2 diabetes to investigate changes in carbohydrate and lipid metabolism in kidney cortex, peripheral nerve, and retina. Our systems approach using transcriptomics, metabolomics, and metabolic flux analysis aims to identify tissue-specific differences in glucose and fatty acid metabolism.

* In collaboration with Subramaniam Pennathur, M.B.B.S. (U-M Department of Internal Medicine; Nutrition Obesity Research Center Molecular Phenotyping Core), Frank Brosius III, M.D. (U-M Department of Internal Medicine and Molecular and Integrative Physiology), and Matthias Kretzler, M.D. (U-M Department of Internal Medicine, Computational Medicine and Biology), we are also identifying lipid biomarkers that lead to the onset diabetic kidney disease, diabetic neuropathy, and diabetic retinopathy in order to elucidate the essential cellular lipid metabolism responses that are amenable to novel therapies.

* In collaboration with Brian Callaghan, M.D. (U-M Department of Neurology), Morten Charles, M.D., Ph.D. (Aarhus University, Aarhus, Denmark), Troels S. Jensen, M.D., D.M.Sc. (Aarhus University), and Reimar W. Thompson, M.D., Ph.D. (Aarhus University), for the International Diabetic Neuropathy Consortium (IDNC), we are addressing the goals of 1) increasing the understanding of basic mechanisms and risk factors in DN, 2) improving the detection and understanding of the clinical course of nerve damage in diabetes, and 3) eventually contributing to the prevention and treatment of DN. The IDNC will ensure an in-depth analysis of basic, epidemiological, and clinical findings of DN, and in addition provide a unique platform for educating future scientists/clinicians within the field.

* In collaboration with Sebastian Parlee, Ph.D. (U-M Department of Physiology) and Michael Dority (U-M Medical School Host Microbiome Initiative), we are using the mouse dietary reversal model to explore the role of pathophysiological local adipose tissue remodeling in HFD-induced neuropathy as well as the role of changes in the intestinal microbiome and their impact on peripheral nerves.

* In collaboration with Celine Berthier, Ph.D., Eddy Sean, Ph.D., and Felix Eichinger, Ph.D. (U-M Department of Internal Medicine), we are using an unbiased bioinformatics clustering method to examine the tissue-specific effects of drugs on the nerves and kidneys during type 2 diabetes.

* In collaboration with Janet Shaw, Ph.D. (University of Utah, Department of Biochemistry), we are studying the involvement of Miro1 and Miro 2 proteins in abnormal mitochondrial trafficking associated with palmitate treatments.

* In collaboration with Guido Cavaletti, M.D. (University of Milan Biccoca, Department of Surgery and Translational Medicine) and Cristina Meregalli, Ph.D. (University of Milan Biccoca, Department of Surgery and Translational Medicine), we are utilizing mitochondrial trafficking techniques to test the efficacy of chemotherapeutic agents.

* In collaboration with Marija Sajic, Ph.D. (University College London, Department of Neuroinflammation), we are evaluating changes in mitochondrial transport in saphenous nerve axons of mice, and also plan to apply this technique to the high fat mouse model.

* In collaboration with Jorge A. Iñiguez-Lluhí, Ph.D. (U-M Department of Pharmacology), we are examining post-translational modifications in the CNS to determine the role of alterations in SUMOylation and ubiquitination in the pathogenesis of sensory neuron degeneration.