Document text
Principal Investigator: Maria Alejandra Vicent Allende
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2024
Award: $53,974
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Traumatic spinal cord injury (SCI) is an acquired disorder causing permanent functional deficits due to lack
of regenerative ability of the central nervous system (CNS). The inability of the CNS to re-generate is in stark
contrast with its ability to generate precise circuitry during development. Corticospinal neurons (CSN) are the
subtype of cortical projection neurons (PN) that normally connect the cerebral cortex to the spinal cord to control
voluntary motor output directly and indirectly. During development, CSN axons traverse vast distances to
establish segmentally-specific functional circuitry along the rostro-caudal spinal cord. Establishment of such
specific circuitry necessitates tightly regulated, dynamic developmental programs to progressively refine CSN
identity and their input and output connections. After injury, CSN do not normally re-establish functional
circuitry. Despite decades of research, and existence of multiple animal models of increased CSN regeneration,
the extent of functional recovery for people with SCI remains largely unchanged. This lack of clinical advance is
partly due to limitations of understanding of molecular mechanisms directly responsible for locally enacting axon
growth and guidance (or not), both during development and during attempted regeneration. In my proposed
work, I will investigate the distinct transcriptomes and proteomes of CSN growth cones (GCs) vs. somata during
development and after injury, toward selecting molecular candidates for functional manipulation.
GCs are the cellular subcompartments at the ends of growing axons that directly enact neuronal subtype-
specific axon growth and guidance during development and after injury. Direct investigation of CSN GC
molecular machinery promises to elucidate local subcellular processes that underpin developmental and
regenerative CSN growth. My lab has recently developed experimental and analytic approaches to deeply
investigate subtype- and stage-specific GCs in vivo. These approaches have led to identification of neuronal
subtype-specific regulation of local RNA, protein, and translation in interhemispheric callosal and
corticothalamic projection neurons. My lab and I have purified thoracolumbar CSN (CSNTL) GCs and somata
from postnatal day 3 (P3), P5, and P7 mice, during axon elongation, grey matter innervation, and branching. I
will analyze the RNA sequencing data obtained, and will expand by addition of proteomics, to select candidates
for functional investigation (Aim 1). I will use a model of increased CSN regeneration after SCI (Pten deletion)
to investigate local RNA-protein of regenerating CSNTL (Aim 2). Why CNS regeneration does not occur after
injury is a critical unanswered, fundamental question with immense translational implications. My work aims to
elucidate developmental growth programs responsible for directing appropriate CSN axon elongation, segment-
specific branching and collateralization, and synapse targeting. Importantly, my work also aims to elucidate
molecular mechanisms responsible for enabling growth of the CNS after injury. Deeper elucidation of molecular
mechanisms of regenerative growth will enable future development of targeted therapies for disability from SCI.
Terms: <21+ years old><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Axon><Body Size><CNS Nervous System><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Matrix><Cellular Physiology><Cellular Process><Central Nervous System><Cerebral cortex><Clinical><Cytoskeletal System><Cytoskeleton><Data><Development><Disabled Persons><Disabled Population><Disease><Disorder><Elements><Environment><Exhibits><Future><Generalized Growth><Genetic><Goals><Growth><Growth Cones><Handicapped><Human><In Vitro><Injury><Intracellular Communication and Signaling><Investigation><Label><Maintenance><Mediating><Medulla Spinalis><Methodology><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Motor output><Movement><Murine><Mus><Natural regeneration><Nerve Cells><Nerve Regeneration><Nerve Unit><Neural Cell><Neuraxis><Neuro-regeneration><Neurocyte><Neurons><Neuroregeneration><Non-Polyadenylated RNA><Output><Parents><People with Disabilities><Persons><Persons with Disabilities><Process><Proteins><Proteome><Proteomics><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Recovery of Function><Regeneration><Regenerative capacity><Regulation><Research><Ribonucleic Acid><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Cord><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Subcellular Process><Synapses><Synaptic><System><Therapeutic><Thoracic Portion of Spinal Cord><Thoracic Spinal Cord><Thoracic spinal cord structure><Tissue Growth><Training><Transcript><Translations><Traumatic Myelopathy><Validation><Work><adulthood><axon growth><axon growth cone guidance><axon guidance><axonal growth><biological signal transduction><body movement><candidate identification><candidate selection><combinatorial><comparative><developmental><disability><disabled individual><disabled people><functional recovery><gain of function><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><global gene expression><global transcription profile><gray matter><in vivo><individuals with disabilities><injured><injuries><innervation><insight><intracellular skeleton><meter><model of animal><nerve supply><nervous system regeneration><neural cell body><neural regeneration><neuron development><neuron regeneration><neuronal><neuronal cell body><neuronal circuit><neuronal circuitry><neuronal development><neuronal growth><neuronal regeneration><neuroregenerative><new approaches><novel approaches><novel strategies><novel strategy><ontogeny><parent><postnatal><postsynaptic><programs><receptor><recruit><regenerate><regenerated nerve><regeneration ability><regeneration capacity><regenerative><regenerative growth><repair><repaired><soma><sub-cellular targeting><subcellular targeting><substantia grisea><synapse><synapse formation><synaptogenesis><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><trafficking><transcriptome><transcriptome sequencing><transcriptomic sequencing><translation><translational progress><translational progression><validations>