Project Details
Description
PROJECT SUMMARY/ABSTRACT
In order to understand neurological diseases, it is essential to identify the affected neuronal cell types,
create model systems that accurately recapitulate normal function and disease phenotypes, and develop tools
that allow cellular manipulations. Motor neurons in the spinal cord control body movement by communicating
central motor commands with muscle targets. All spinal motor neurons are born and specified during embryonic
development, but their molecular identities and electrophysiological properties evolve for weeks in mice and
months in humans, until motor circuits and behavior become fully mature in post-natal life. In diseases like
Amyotrophic Lateral Sclerosis (ALS), sarcopenia, or spinal cord injury, the degeneration of specific subsets of
mature, adult motor neurons can lead to loss of muscle control, paralysis, and death. Although several studies
have mapped the mechanisms of motor neuron diversification in the embryonic spinal cord, our understanding
of motor neuron diversity in the adult spinal cord is in its infancy. This hinders the study of adult motor neuron
diseases as the affected motor neuron subtypes are not thoroughly defined. Furthermore, in vitro models that
faithfully recapitulate adult motor neuron identity do not exist, and adequate tools to access specific motor neuron
subtypes in vivo are lacking. This research plan aims to map the trajectory of post-mitotic motor neurons from
embryo to adulthood and use this data to both create viral tools that provide genetic access to specific subtypes
of motor neurons in vivo, and develop methods for generating adult-like motor neurons in vitro. This will be done
by first performing single cell transcriptome and chromatin profiling in mouse spinal motor neurons at various
embryonic to adult ages. The temporal chromatin profiles will be used to develop AAV tools that provide genetic
access to specific motor neuron subtypes at all ages, and to computationally identify candidate regulators of
subtype- and adult-specific identity. The identified regulators will then be used to mature the age of mouse stem
cell derived motor neurons in vitro. Finally, single cell transcriptomic and chromatin accessibility profiles of adult
human motor neurons will be generated and a combination of mouse and human-specific regulators will be used
to program the age of iPSC-derived motor neurons. This thorough approach will define the molecular features
of motor neuron subtypes that contribute to their differential susceptibility in disease, and establish tools
necessary for dissecting circuits, disease modeling, and the delivery of potential therapeutics.
The training phase of the award will be conducted in the laboratory of Dr. Hynek Wichterle at Columbia
University, and under the co- mentorship of Dr. David Gifford and Dr. Paola Arlotta. My career development plan
describes a detailed timeline for acquiring all the technical and professional skills necessary for the successful
transition into a career as an independent researcher. The completion of the proposed research plan will facilitate
future research in my lab aimed at understanding the temporal dynamics of neuronal identity, circuits, and
disease in motor neurons and other nervous system cells.
Status | Finished |
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Effective start/end date | 1/1/24 → 12/31/24 |
Funding
- National Institute of Neurological Disorders and Stroke: $224,100.00
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