Safadi Program of Excellence in Clinical and Translational Neuroscience
Whether in clinical care or medical research, it is critical for physicians and scientists to partner in order to make important advances. This is particularly true in the neurosciences, where the brain presents an immense frontier for scientific advances utilizing collaborative tools and integrative strategies. The Safadi Program of Excellence in Clinical and Translational Neuroscience at the University of Chicago Medicine was launched on April 18, 2017, with the aim of facilitating this multidisciplinary interface, and creating opportunities for collaboration among scientists and clinicians engaged in the diagnosis and treatment of neurological disorders. (Learn more about Mr. Mohammad Safadi.)
Serving as a bridge between clinical disciplines engaged in the care of neurological diseases, including neurology and neurosurgery, the Safadi Program will further our understanding of the underlying biology of the nervous system and translate those novel findings to improve patient care. In addition, the Safadi Program will catalyze partnerships with groups across the University, enabling cross-disciplinary thinking that will allow us to tackle the most complex problems in the field.
Hosted by the Safadi Program of Excellence in Clinical
and Translational Neuroscience at the The University of Chicago Medicine
“One Brain, Many Genomes: Somatic Mutation and Genomic Diversity in The Human Brain, From Development to Degeneration”
Christopher A. Walsh, MD, PhD
Bullard Professor of Pediatrics and Neurology
Harvard Medical School
Chief of the Division of Genetics and Genomics
Boston Children's Hospital
Investigator of the Howard Hughes Medical Institute
Annual Safadi Lecture
Wednesday September 15, 2021
11:30 AM – 1 PM (CDT)
Dr. Walsh completed his MD and PhD degrees at the University of Chicago, neurology residency and chief residency at Massachusetts General Hospital, and postdoctoral training in Genetics with Connie Cepko at Harvard Medical School. In 1993 he became Assistant Professor of Neurology at Harvard and Beth Israel Deaconess Medical Center. From 2003-2007 he served as
Director of the Harvard-MIT Combined MD-PhD training program. He moved to Boston Children’s Hospital in 2006, becoming Chief of Genetics. Dr. Walsh’s research has focused on the development and function of the human cerebral cortex, pioneering the analysis of genetic diseases that affect the developing brain, resulting in epilepsy, intellectual disability, autism spectrum disorders (ASD), and other conditions. His lab has identified more than three dozen neurological disease genes, and described how a few of these disease genes were important targets of the evolutionary processes that shaped the human brain. Recent work has pioneered the understanding of clonal somatic mutations as a cause of focal epilepsy and a portion of ASD, and the wide genomic diversity of neurons in human brain. Dr. Walsh’s research has been recognized by a Javits Award from the National Institute of Neurological Disorders and Stroke, the Dreifus Penry Award from the American Academy of Neurology, the Derek Denny-Brown and Jacoby Awards from the American Neurological Association, the Research Award from the
American Epilepsy Society, the Pruzhansky Award from the American College of Medical Genetics, the Cajal Club Discoverer Award, the Perl-Neuroscience Award from the University of North Carolina, and the Distinguished Alumni Award from the University of Chicago. Dr. Walsh is an elected fellow of the American Association for the Advancement of Sciences, and a member of the American Association of Physicians, the National Academy of Medicine, the American Academy of Arts and Sciences, and the National Academy of Sciences.
Safadi Program Director
John Harper Seeley Professor of Surgery, Neurology & The Comprehensive Cancer Center
Director, Neurovascular Surgery
Professor of Neurology
Chair, Department of Neurology
Professor of Surgery
Director, Neurosurgical Oncology
Interim Chair, Department of Neurological Surgery
Director, Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior
Albert D. Lasker Professor
Executive Director, Bucksbaum Institute of Clinical Excellence
Lindy Bergman Distinguished Service Professor of Medicine and Surgery
Director, MacLean Center for Clinical Medical Ethics
Director, Institute for Translational Medicine
Walter L. Palmer Distinguished Service Professor of Medicine and Pediatrics
Dean for Translational Medicine, Biological Sciences Division
Vice Chair for Research, Department of Medicine
Chair, Committee on Molecular Medicine
Professor of Pediatrics
- UChicago Medicine Neurosciences programs
- UChicago Medicine Department of Neurology
- UChicago Medicine Section of Neurosurgery
- Institute for Translational Medicine
- Bucksbaum Institute for Clinical Excellence
- UChicago Medicine Comprehensive Cancer Center
- Argonne National Laboratory
- Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior
- Institute for Molecular Engineering
- UChicago Department of Neurobiology
Deadline for Submission: December 1, 2020
Project Period: Maximum 12 months, to commence any time after January 1, 2021
Full time faculty in any track at the University of Chicago are invited to apply for Safadi Pilot Grants, to support the generation of preliminary or exploratory data involving novel multidisciplinary neuroscience collaborations, or to help support fellowship training involving novel multidisciplinary tools and concepts.
Proposals should articulate the novel multidisciplinary collaboration, and disease relevance or collaboration with clinical neuroscience group. Applications are due at midnight, December 1, 2020. Decisions about winning proposals will be made before January 1, 2021, and funding for up to 12 months may be requested to commence any time after that date.
Proposals will be evaluated based on:
- Scientific rigor
- The uniqueness of opportunity/infrastructure/milieu
- Contribution to multidisciplinary program development, specifying what disciplines it proposes to bridge
- Potential impact on clinical neuroscience translation or disease applications
- Future directions (ie how pilot data will be used for future project application; or how would fellowship support will be leveraged in future career development in multidisciplinary perspective).
2021 Safadi Pilot Grant Awards
Twelve applications for pilot awards were received by the deadline. Eleven qualifying applications were reviewed by three reviewers (intramural and extramural distinguished faculty spanning multiple neuroscience fields). Each proposal was graded in 6 domains (innovation, scientific rigor, uniqueness of opportunity/ infrastructure/ milieu, multidisciplinary perspective enriching/broadening neuroscience, translational potential clinical/disease relevance, and future direction/impact/potential).
The best scoring applications were programmatically reviewed for feasibility and budget. This year’s submissions were particularly competitive, scoring an amazing mean of 2.4 (on a scale of 1/best to 5/worst), with a range of 1.8 to 3.4. With conservative stewardship of the Safadi Pilot funds in recent years, and budget adjustments to awarded grants, were able to recommend five proposals, scoring between 1.8 and 2.2, for funding. This is the largest number of Safadi pilot grants funded in any given year!
Congratulations a truly exceptional slate of winning proposals, bridging multiple disciplines, and blazing new trails of multidisciplinary collaborations.
Alfredo J. Garcia, PhD
Department of Medicine (Emergency Medicine) and The Grossman Institute
In collaboration with the institute of Integrative Physiology
Neural Mechanisms of Respiratory Instability Due to Chronic Fentanyl Use
While we have extensive insights into acute respiratory depression, the hallmark trait of opioid overdose, a significant gap in knowledge exists for understanding how chronic opioid use remodels brain networks involved with the control of breathing. Using a model recapitulating many respiratory phenotypes associated with chronic opioid use, our work will investigate the neurophysiological remodeling of respiratory brainstem networks at the single cell and circuit levels. Completion of this work will provide critical understanding into the neuronal mechanisms that contribute to the morbidities and mortality in the ongoing opioid crisis.
Romuald Girard, PhD
Neurovascular Surgery Program, Department of Neurological Surgery
In collaboration with the Departments of Neurology, Public Health Sciences, and Diagnostic Radiology, and the Center for Research Informatics
Machine Learning Analyses of in-vivo Brain Permeability and Iron Deposition in the Human Brain with Hemorrhagic Angiopathy
Hemorrhagic micro-angiopathies (HMAs) are age-related subtle brain bleeds affecting a fourth of the worldwide aging population, and predisposing to hemorrhagic stroke and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Little is known about mechanisms and biomarkers of HMAs, needed to ultimately lessen their public health impact. This research project assesses brain permeability and iron content in aging patients with and without HMA, as a first step to identify human subjects at higher risk of brain bleeding.
Stephanie Hage, MD (2021), MSc, MA
Postdoctoral Fellowship Support
Neurovascular Surgery Program, Department of Neurological Surgery
In collaboration with the Departments of Neurology, Public Health Sciences, and Diagnostic Radiology, and the Johns Hopkins University Brain Injury Outcomes Section and Biostatistics
Bayesian Adaptive Design in Phase IIA Biomarker Trial
Multidisciplinary career development plan and data simulations in an ongoing clinical trial funded by the National Institutes of Health, to assess the impact of therapy on multiple biomarkers of disease. This represents a novel framework for integrating novel biologic signals (ie. metabolomics, proteins, microRNA, cell free DNA) as surrogate outcomes in a therapeutic trial, and will be broadly applicable to other diseases.
Martin Herman, MD, PhD
Spine Program, Department of Neurological Surgery
In collaboration with the Departments of Neurology, Diagnostic Radiology, Pathology, Organismal Biology and Anatomy, and the Animal Research Center; Biomedical Engineering and Prosthetics Research at the Illinois Institute of Technology at the University of Illinois at Chicago; and Physical Medicine and Rehabilitation at the University of Alberta, Canada
Implantation of Wireless Floating Multielectrode Arrays into Lumbar Spinal Cord for the Control of Locomotion in Yucatan Pigs
Recovery of function following spinal cord injury remains a daunting medical challenge, and over half of people do not recover the ability to walk. Electrodes implanted into the region of the motor neurons in the spinal cord have demonstrated potential to restore walking in pigs and monkeys, but the externalized wires limit range of movement and include risks of spinal fluid leak and infection. This pilot study explores whether completely internalized 16-channel wireless multielectrode arrays can be surgically implanted in pigs, and if successful, lumbar spinal cord stimulation may recreate locomotion in paraplegic human trials in the future.
Xiaoxi Zhuang, PhD
Department of Neurobiology
In collaboration with the Department of Pediatrics (Pediatric Neurology)
The Contribution of Mild Pyridoxine 5’-Phosphate Oxidase (PNPO) Deficiency to Epilepsy in Children
Vitamin B6 deficiency causes epilepsy that does not respond to commonly prescribed treatments. However, vitamin B6 could be the simple and effective treatment. Our data suggest that the prevalence of this type of epilepsy may be underestimated, especially in pediatric epilepsy patients. We will collect pediatric epilepsy patient saliva samples to do genetic testing of mutations that can cause vitamin B6 deficiency.
Thirteen applications for pilot awards were received. These were reviewed by three reviewers, grading each submission in 6 domains (innovation, scientific rigor, uniqueness of opportunity/ infrastructure/ milieu, multidisciplinary perspective enriching/broadening neuroscience, translational potential clinical/disease relevance, future direction/impact/potential). This year’s submissions were particularly competitive, scoring an amazing mean of 2.67 (on a scale of 1/best to 5/worst), with a range of 2.0 to 3.6. The winning award scored a best 2.0 (with three proposals tying for second with scores of 2.2).
Congratulations a truly exceptional winning proposal bridging developmental neurobiology, endocrinology/diabetes genetics, neurophysiology/ structural biology, and the use of innovative patient-derived cerebral organoids model.
Siri Atma W. Greeley, MD, PhD
Associate Professor of Pediatrics
"Examining the neurodevelopmental role of
KCNJ11 in patient-derived cerebral organoids"
Mutations in the KATP potassium channel gene KCNJ11 are the most common cause of neonatal diabetes, which occurs rarely in babies under 6 months of age. A molecular diagnosis can be transformative for these patients, who can be treated with sulfonylurea pills instead of insulin injections. However, our clinical research over the past decade has shown that the majority of these patients exhibit a range of neurodevelopmental difficulties ranging from mild learning disorders to severe cognitive dysfunction, autism and seizures. We hypothesize that these neurological deficits have prenatal developmental origins resulting from brain expression of mutated KATP channels. To address this, we developed patient-derived cerebral organoids from induced pluripotent stem cells (iPSCs). Cerebral organoids are self-organized tissues that employ the processes that are unique to human cortical development. These organoids permit the study of molecular and cellular machinery that is largely inaccessible by other conventional methods. When derived from patients, this platform can serve to better inform clinical practice.
Dr. Greeley is currently Associate Professor of Medicine and Pediatrics. “As a result of the Safadi pilot grant, We have been able to submit abstracts and present at several scientific meetings, and are in the advanced stages of editing manuscripts that we expect to be submitted in 2021. Pilot results have been very promising, and we are also currently formulating plans for grant submission, which we hope to do within the coming year”.
Ten applications were received by the designated deadline, reviewed and scored by three senior neuroscientists.
Bakhtiar Yamini, MD earned the best composite score among a strong class of applicants, while Hemraj B. Dodiya, PhD and Dongdong Zhang, MD tied for second. Scoring was reflected through the summed grades on: (1) innovation; (2) scientific rigor, (3) uniqueness of opportunity, infrastructure, milieu; (4) multidisciplinary perspective, broadening neuroscience; (5) translational potential, clinical and disease relevance; and (6) future direction, impact potential.
We are very excited about the breadth and potential integrational and translational impact of these projects. Congratulations to our awardees!
"NF-κB and the Microbiome in Neurodegeneration"
Inflammation is one of the most important factors underlying the development of neurodegenerative disease. Although the gut microbiome plays a central role in promoting tissue inflammation, the mechanism by which the microbiome modulates inflammatory signaling is unknown. One of the critical regulators of inflammation is the molecule NF-κB, a factor that increases in human tissue with advancing age. In this study, we propose to examine whether changes in the gut microbiome alter the NF-κB response in the brain leading to cellular senescence. Successful completion of this project will provide useful information on the mechanism by which the gut alters signaling in distant organs, data that will ultimately improve our understanding of the mechanism underlying aging and the development of neurodegenerative disease.
Dr. Yamini is currently Professor and Interim Chair of the Department of Neurological Surgery. “The Safadi award was instrumental in allowing my lab to expand its scope to study the microbiome and its role in modulating NF-κB in the brain. Animal experiments have been completed and the data organized. The results will be included in a future manuscript and will also form the basis of a larger grant.”
"Role of Intestinal Hyperpermeability “leaky gut” in Alzheimer’s Disease Pathogenesis"
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most prevalent form of dementia. The pathogenic role of neuroinflammation is well recognized in the field of neurodegenerative diseases, including AD. However, the biological source(s) that drive neuroinflammation and underlying mechanisms have not been elucidated. Dr. Dodiya proposes that intestinal hyperpermeability, also known as “leaky gut” could be that biological source. Leaky gut is defined as translocation of microbes and/or their metabolites into periphery, which in turn can trigger inflammation at the distal site such as brain. Under Drs. Sangram S. Sisodia and Le Shen’s mentorship, Dr. Dodiya will perform pilot studies to investigate the exact role of leaky gut in AD pathogenesis. These research studies promise to uncover a new mechanism targeting the gut-brain axis in AD pathogenesis. The research establishes novel collaborations between neurobiology, neurosurgery, and digestive diseases research labs.
Dr. Dodiya is a postdoctoral scholar in the Department of Neurobiology. “Support by the Safadi award allowed me to investigate the effect of increased intestinal permeability on Alzheimer's amyloid pathology using DSS colitis Alzheimer's transgenic mouse model. Additionally, in collaboration with Dr. Le Shen (Department of Surgery), I generated APPPS1-21/Occludin KO mice. These mice are currently being evaluated for Alzheimer's histopathology. The data will be submitted to a high impactl journal, and I plan to utilize them for K99/ROO grant submission to the National Institute of Aging”.
"The Antigen Recognition Study in Cerebral Cavernous Malformation Disease"
Cerebral cavernous malformations (CCMs), present in 1,000,000 Americans, can trigger brain bleeding, seizures, headaches, limb weakness, etc. A role was shown for immune cell involvement in CCM disease from our previous studies revealing robust immune cell, antibody presence and specific B-immune cell clonal expansion in CCMs, and reduction of CCM maturation in B-cell depleted mouse models of CCMs. Dr. Zhang will investigate the identity and localization of specific substances (antigens) that trigger the immune response in CCMs. For this project, he will use artificial antibodies generated from the variable genetic sequences of antibodies from immune (plasma) cells isolated from surgically resected CCMs from patients. He labeled these antibodies to visualize the presence in other human CCMs.
To localize the antigen, Dr. Zhang will double label additional CCMs and normal brain tissue with the artificial antibodies and markers of blood vessels, nerve cells, and structures outside of the cells. Using artificial antibodies, he will separate antigens from ground-up human CCMs. He will digest the antigens into protein fragments and determine the molecular weight of these fragments by mass spectrometry to characterize this antigen. This may open novel therapeutic venues in CCM disease.
Dr. Zhang has returned to Harbin Medical University in China, where he is now a neurosurgery resident and is preparing to defend his PhD thesis. “As a result of the Safadi grant, I was able to complete important research at the University of Chicago, identifying key antigens which trigger the defined pathogenetic immune response in cavernous angiomas. Results were published in the Journal of Autoimmunity, and will comprise an important part of my PhD thesis. I am now well on my way to develop as a neurosurgeon scientist at my home institution in China”.
Fifteen applications were received by the designated deadline, reviewed and scored by three senior neuroscientists, two from the university of Chicago and one extramural reviewer. Two applications tied for best composite score, reflecting summed grades on (1) innovation; (2) scientific rigor, (3) uniqueness of opportunity, infrastructure, milieu; (4) multidisciplinary perspective, broadening neuroscience; (5) translational potential, clinical and disease relevance; and (6) future direction, impact potential. Congratulations to our two awardees!
EFFECT OF CEREBRAL CAVERNOUS MALFORMATION GENES ON INTESTINAL EPITHELIUM
Cerebral cavernous malformation (CCM) is a cause of brain hemorrhage at young age. Mutations in CCM disease genes cause disruption of brain endothelial barrier, and leaky junctions between individual small blood vessel cells. Given potentially similar mechanisms maintaining gut epithelial barrier, Dr Shen proposes that patients with CCM mutations also have a leaky gut, and may be predisposed to inflammatory bowel disease. He will perform pilot studies to test if mutations of these genes also affect cell-cell connections in epithelium.He will initiate animal models of inflammatory bowel disease, where CCM mutations can be tested in mice, and he will show feasibility of analyzing the fecal specimens of patients with familial CCM disease, to confirm whether their microbiome reflects increased gut permeability. The research establishes novel collaborations between the neurosciences and the rich digestive and microbiome research communities at the University of Chicago. It promises to uncover a new mechanism of gut disease, through the actions of brain disease genes.
Dr. Shen is currently Research Associate Professor in the Department of Surgery. “The Safadi Award helped me advance my career tremendously. It allowed me to publish multiple high impact papers (FASEB, Lab Invest, Acta Neuropathol Com, Science Transl Med, and Nature Com) and receive federal funding from the U.S. Department of Defense to study the role of CCM proteins in the gastrointestinal system. The Safadi Award support turned this line of research into a major focus for my future investigations”.
DIFFERENTIAL TRANSCRIPTOME OF HUMAN CEREBRAL HEMORRHAGIC MICROANGIOPATHY
Hemorrhagic stroke results from the weakening of small brain blood vessels, often many years preceding the symptomatic event. Ample opportunities to prevent a lethal or disabling stoke are presented by known mechanisms governing the weakening of blood vessels, many of which are reflected by differentially expressed genes in weakened blood vessels. Dr Polster proposes to build on expertise and infrastructure in the Neurovascular Surgery Research laboratory with differential transcriptome of diseased endothelium, the lining of blood vessels, in genetic diseases predisposing to hemorrhagic stroke. He will use laser capture microdissection to isolate endothelium from sample autopsy specimens of human brain tissue with hemorrhagic brain lesions and isolate their RNA. He will analyze the differentially expressed genes in this tissue in comparison to normal human brain vessel lining, and datasets from the genetic diseases already studied. He hopes to define common genes defining leaky blood vessels, and these can serve to identify biomarkers of disease in future career development project.
Dr. Polster is completing a post-residency fellowship, in preparation for faculty position as a neurosurgeon-scientist. “As a direct result of the Safadi Program Award our team was able to pursue a better understanding of commonalities of cerebral cavernous malformation (CCM) and the aging brain with propensity to hemorrhage. Using CCM with known mechanisms, imaging biomarkers, gut-brain axis, and emerging therapeutics we have identified similar gene disturbances, blood and imaging biomarkers in the aging brain. As faculty I plan to use the data and knowledge generated by the Safadi Pilot to obtain NIH funding and further pursue research that brings understanding and possibly shared therapeutics to diseases of the brain”.