Identifying Disease Mechanisms in Neurodegeneration using Genomics and Bioinformatics

Daniel Geschwind, MD, PhD
University of California, Los Angeles (Los Angeles, CA)

Co-Principal Investigators

Jessica Rexach, MD, PhD
University of California, Los Angeles (UCLA) (Los Angeles)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2018700S
Award Type:
Standard
Award Region:
US Southwestern

Understanding Glial Signaling in Neurodegeneration via Gene Network Analysis

Summary

Recent scientific discoveries suggest that multiple cell types might participate in Alzheimer’s disease (AD), and understanding the key players and their effects on dementia would advance our ability to design new drugs and therapies. However, the complexity of the brain’s different cell types presents a unique challenge to scientific inquiry. Here I propose work to bridge the divide by using cutting edge technology to profile the different cells of the dementia brain at unprecedented resolution. The results of this work will be new candidate drug targets for dementia and a new approach for studying complex brain diseases. 

Details

Alzheimer’s disease (AD) has traditionally been studied one gene, cell type, or biological process at a time; however, it is increasingly clear that this disease involves multiple interacting cell types and pathways within those cells. We currently lack a refined view of AD from the cellular and multicellular levels. Such an understanding would advance data driven approaches to identify disease mechanisms and inform rational drug design. Transcriptomic network analysis and functional genomics approaches performed at the whole tissue level have uncovered a complex role for neuron-glial interactions.  However, glial contributions to disease are particularly challenging to identify by these methods in whole tissue alone due to complex transcellular interactions and functional heterogeneity among glia, for example, microglia and astrocytes.  The objective of this proposal is to complete longitudinal single-cell transcriptional profiling and integrate the results with data from mouse models and human disease, to add the cellular resolution needed to fully leverage transcriptomic networks to understand glial signaling mechanisms in AD.

About the Researcher

Dr. Geschwind earned his BA degree in chemistry (modified with psychology) at Dartmouth College in 1982. He subsequently entered the MD-PhD program at Yale University School of Medicine, earning his medical degree and doctoral degree in neurobiology in 1991. He completed a residency in neurology at UCLA and joined the faculty in 1997. His laboratory has pioneered the application of systems biology methods in neurologic and psychiatric disease, working in collaboration with dozens of other laboratories to connect molecular pathways to nervous system function. His work’s main goal is to develop new therapeutics for nervous system disorders for which disease-altering therapies are not currently available.  In his capacity as senior associate dean and associate vice chancellor of Precision Health, he leads precision health and genomic medicine activities at UCLA.

Dr. Geschwind has published over 400 papers and serves on the editorial boards of Cell, Neuron, and Science.  He has also received numerous awards, including the Derek Denny-Brown Neurological Scholar Award from the ANA in 2004, the Scientific Service Award from Autism Speaks in 2007, the Ruane Prize from the Brain and Behavior Foundation in 2013, and the New Innovators Award from Amgen in 2018. His is an elected Member of the American Association of Physicians and the National Academy of Medicine.

Personal Story

I grew up in a family surrounded by scientists, including my father, who was a solid-state physicist and his cousin, Norman Geschwind, a founder of the field of behavioral neurology.

In spite of this background and the fact that I had always been fascinated by the brain, my path was anything but direct. My mother, who was an artist, felt that medicine was too stressful and urged me to find balance in life. So, following college, I spent a fascinating two years at the Boston Consulting group, where I explored the world of business and corporate strategy. It was a fantastic experience, but I also realized that my “calling” was in medicine and biomedical research.

In medical school at Yale, I also obtained a PhD in developmental neurobiology, and was interested in both psychiatry and neurology as clinical disciplines. In the end, the pull towards internal medicine led me to neurology, but I came to UCLA because of the history of a close relationship of the two disciplines.  In both fields, the major hope for disease-altering therapies lies in basic and translational research, so I always knew that I would be focusing my time on research. In residency, I had the good fortune to work with the extraordinary clinician-scientist, Bruce Miller, who exposed me to frontotemporal dementia and related disorders, and we began to work on the genetics of these dementias. We also began to work on autism, which at the time was an area that had not been well explored by geneticists or neurobiologists.

My lab was an early adopter of unbiased genetic and genomic approaches, which I felt were important to use, given how little we truly understand about brain function. We have continued to develop and apply genomic and computational methods to rationally inform hypothesis-testing experiments, rather than taking the position that we know enough to study one gene at a time. This led to a series of unbiased transcriptome measurements combined with network analysis that have led to new understanding in developmental and neurodegenerative disorders. This is especially important in dementia research, where my opinion is that dominant hypotheses have restricted development of new hypotheses and drug targets. The work funded by BrightFocus is at the cutting edge of these efforts to refine our understanding of neuro-inflammation, which growing evidence supports as playing a clear causal role in neurodegeneration. 

More Information


About Jessica Rexach, MD, PhD

Dr. Rexach earned her BA degrees in Chemistry and Biology at Cornell University in 2003. She subsequently entered the joint MD PhD program between California Institute of Technology and University of California, Los Angeles, completing her medical degree and doctoral degree in Neuroscience (with a research focus in Chemical Biology) in 2012.  Her graduate work resulted in three first author publications in Nature Chemical Biology. She completed a medical internship at Cedars Sinai Medical Center and a residency in Neurology at University of California, Los Angeles. She subsequently completed a competitive NIH-sponsored joint research and clinical fellowship in Neurogenetics and Neurobehavior at University of California, Los Angeles. Dr. Rexach is currently an attending physician in the UCLA Neurogenetics Program with clinical specialty in neurodegenerative disorders affecting cognition and dementia.  She is concurrently completing her postdoctoral research training in the laboratory of Dr. Geschwind. Dr. Rexach’s research uses human genetics and systems biology to understand immune signaling in Alzheimer’s and associated dementias with the goal of developing immune-targeted therapies.

Throughout her education and training, Dr. Rexach has been recognized for excellence in teaching, clinical care, and science.  She has received numerous awards including the August Rose Award for Excellence in Teaching and J. Louis Riehl Research Award from the UCLA Department of Neurology, Leo G. Rigler Award for Oustanding Achievement as a medical intern from Cedars Sinai Medical Center, Emil Bogen Research Prize from the UCLA School of Medicine, and Leo and Berdie Mandelkern Prize in Chemistry from Cornell University.

Dr. Rexach's Personal Story

I was born a city girl but my formative years were spent in the mountains of California’s gold country in the small and quiet town of Mariposa.  Even as a child, I had an unstoppable internal drive to share my ideas and contribute to fixing big problems in the world. The desire to make a difference in dementia led me on my path as a physician scientist. I believe a physician scientist is tasked to seek out, adopt or create whatever scientific tools are necessary to meet their clinical goal.  The caveat is that this takes exceptional mentorship and training to achieve. It is from that view that I chose to train in Chemical Biology under Linda Hsieh-Wilson at California Institute of Technology and develop skills in creating chemical and biological tools to meet gaps in molecular biology. It was the same view that led me to expand into systems biology, genetics, and bioinformatics with my post-doctoral research training, in order to develop the skills to use human data to guide my experimental science.  In this work, I have had the remarkable privilege to train under Dr. Daniel Geschwind who is a pioneer in applying systems biology and data science to tackle the critical unknowns in neuropsychiatric disease.  This data-driven approach has led me to the study of immune signaling and the interaction of different brain cell types in dementia. I reason that immune signals offer key access points for the development of clinical biomarkers and drug development in dementia, and that a systems view will provide insightful perspective on how to address the rational design of dementia therapies.  

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