2018 HARVARD CATALYST
PROGRAM FOR FACULTY DEVELOPMENT AND DIVERSITY INCLUSION (PFDD)
FACULTY FELLOWSHIP - HMS
Steven Rodriguez, PhD
Instructor, Massachusetts General Hospital
Department of Biological Chemistry and Molecular Pharmacology
Mentor: Mark W. Albers, MD, PhD, Assistant Professor of Neurology, Frank Wilkens Jr. and Family Endowed Scholar in Alzheimer’s Disease Research, Massachusetts General Hospital
Department Chair: Merit Cudkowicz, MD, Julieanne Dorn Professor of Neurology, Head of the Department of Neurology, Massachusetts General Hospital
Project Title: “Preclinical identification and validation of a novel inflammatory signature as biomarkers for the treatment of ALS”
Project Description: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that progressively erodes neurons in the brain and spinal cord. Current therapies only offer modest benefits to ALS patients, necessitating a better understanding of the mechanisms of neurodegeneration. We have identified a novel mechanism in ALS that is initiated by genomeencoded dsRNA that activates a neuroinflammatory antiviral innate immune pathway, leading to neurodegeneration. We developed and screened a neural culture model system of dsRNAmediated neurotoxicity and we identified an FDA-approved drug that rescues neurotoxicity. We will determine if this drug can reduce neurodegeneration in an animal model before it can be tested in a clinical trial for ALS. Additionally, it will be essential to identify mechanistic biomarkers for efficacy of this drug in patients. Based on work in the literature and our work, we initially propose to test if a panel of 4 biomarkers found in the CSF of ALS patients that are elevated by dsRNA-mediated signaling. We will examine the effectiveness of the drug to decrease the expression of these biomarkers in our culture model. Working with collaboration with computational scientist we identified an additional 25 secreted proteins by mass-spec based proteomics, whose expression is increased by dsRNA. We will further test if these can be novel mechanistic biomarkers for drug activity. This study will help determine if an FDA-approved drug we found to rescue dsRNA-mediated toxicity is a viable option as a therapeutic drug for ALS patients.
Biography: Steven Rodriguez, Ph.D., is an Instructor in the Department of Neurology at Massachusetts General Hospital. Steven was born and raised in Bronx, NY. He completed his B.A. from Queen's Collage CUNY. Steven got his Ph.D. studying the development and connectivity of neurons in the mouse olfactory neural circuit in the lab of David Lin at Cornell University. During his work he elucidated a non‐cell‐autonomous role for Notch2, a gene known for its role in development, in maintaining neuronal viability in adult mice. This work got him interested in studying mechanisms of neurodegeneration. He did a postdoctoral fellowship under the guidance of Dr. Mark Albers at the Institute for Neurodegenerative disease at MGH. In Mark’s lab, he uses the main olfactory system and human cultured neurons to study mechanisms of neurodegeneration. He found a novel mechanism of neurotoxicity mediated by DNA damage induced activation of antiviral innate immune pathways. Steven also became a member of the Lab of Systems Pharmacology at Harvard Medical School where he continues to work on the role of antiviral signaling in neurodegeneration and on identifying therapeutic approaches to treat neurodegenerative disease.