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Principal Investigator: Polyxeni Philippidou
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $333,915
Funding agency: National Institute of Neurological Disorders and Stroke
Breathing is the most fundamental motor behavior for terrestrial vertebrates. The frequency and amplitude of
breathing movements are controlled by neural networks residing in the brainstem and spinal cord. In mammals,
contraction of the diaphragm muscle is essential for driving airflow into the lungs during inspiration. Despite the
complexity of the neural networks that regulate respiratory rhythms, diaphragm contraction is controlled by a
single motor input, the activity of motor neurons (MNs) within the Phrenic Motor Column (PMC) in the cervical
spinal cord. Loss of PMC neurons is the primary cause of death in degenerative MN diseases such as
amyotrophic lateral sclerosis (ALS) and spinal cord injuries. Despite their essential role, the molecular
determinants of PMC neuron identity are largely unknown. We have found that the development of PMC neurons
requires the sustained activity of Hox5 transcription factors. Mice lacking Hox5 genes in MNs die of respiratory
failure at birth and exhibit defects in multiple aspects of PMC identity, including cell body position, axon guidance
and diaphragm innervation. In this proposal we will investigate the function of Hox5 genes in determining and
maintaining phrenic MN identity.
In Aim 1 we will determine temporally distinct functions of Hox5 proteins in phrenic MNs and how phrenic MN
identity is maintained throughout lifetime.
In Aim 2 we will define how Hox5 genes control phrenic MN specification at the transcriptional level.
In Aim 3 we will identify direct Hox5 effectors and dissect their regulatory mechanisms.
We have developed an integrative methodology encompassing genetic models, high-throughput sequencing,
electrophysiology and behavioral assays, such as plethysmography, to address these questions in vivo. The
overarching goal of this proposal is to uncover the basic principles underlying phrenic MN specification and
maintenance so that we can begin to consider alternative treatment methods for respiratory dysfunction.
Terms: <21+ years old><Abscission><Address><Adult><Adult Human><Air Movements><Airway failure><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Assay><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Behavior><Behavioral Assay><Binding Sites><Bioassay><Biological Assay><Birth><Brain Stem><Brainstem><Breathing><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cause of Death><Cell Body><Cells><Cerebroatrophic Hyperammonemia><Cervical Portion of Spinal Cord><Cervical Spinal Cord><Cervical spinal cord structure><ChIP Sequencing><ChIP-seq><ChIPseq><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Collagen><Combining Site><Connector Neuron><Cot Death><Crib Death><Defect><Degenerative Neurologic Disorders><Development><Diaphragm><Disease><Disorder><Electrophysiology><Electrophysiology (science)><Embryo><Embryonic><Enhancers><Excision><Exhibits><Extirpation><Extremities><Frequencies><Gehrig's Disease><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Diseases><Genetic Models><Genetic Transcription><Goals><HOX gene><HOX protein><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Homeo Box Genes><Homeobox Family Gene><Homeobox Genes><Homeodoamin Gene><Homeotic Genes><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Lead><Life><Limb structure><Limbs><Locomotor Activity><Lou Gehrig Disease><Lung><Lung Respiratory System><Maintenance><Mammalia><Mammals><Maps><Mediating><Medulla Spinalis><Membrane><Metabolic><Methodology><Methods><Mice><Mice Mammals><Molecular><Motor><Motor Activity><Motor Cell><Motor Neuron Disease><Motor Neurons><Movement><Murine><Mus><Muscle><Muscle Tissue><Muscular Dystrophies><Mutant Strains Mice><Myodystrophica><Myodystrophy><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Neurophysiology / Electrophysiology><Non-Trunk><POU transcription factor Oct-6><Parturition><Pathway interactions><Pattern><Pb element><Perinatal Mortalities><Perinatal lethality><Perinatal mortality demographics><Plethysmography><Predisposition><Proteins><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Regulatory Element><Removal><Repression><Respiration Disorders><Respiratory Aspiration><Respiratory Diaphragm><Respiratory Disorder><Respiratory Failure><Respiratory Inspiration><Respiratory physiology><Rett Disorder><Rett Syndrome><Role><SCIP protein><SIDS><Sleep Apnea><Sleep Apnea Syndromes><Sleep Hypopnea><Sleep-Disordered Breathing><Specific qualifier value><Specified><Spinal><Spinal Cord><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Sudden Infant Death><Sudden Unexpected Infant Death><Sudden infant death syndrome><Surgical Removal><Susceptibility><Synapses><Synaptic><Testing><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Traumatic Myelopathy><Vertebrate Animals><Vertebrates><adulthood><air flow><airflow><alternative treatment><axon growth cone guidance><axon guidance><body movement><body position><breathing disorder><chromatin immunoprecipitation-sequencing><cofactor><coping><degenerative diseases of motor and sensory neurons><degenerative disorder of motor neurons><degenerative neurological diseases><developmental><developmental disease><developmental disorder><driving><electrophysiological><genetic approach><genetic condition><genetic disorder><genetic strategy><heavy metal Pb><heavy metal lead><improved><in vivo><innervation><insight><inspiration><membrane structure><motoneuron><motor behavior><motor neuron development><mouse mutant><muscle dystrophy><muscular><nerve supply><neural circuit><neural circuitry><neural network><neurocircuitry><neurodegenerative illness><neuronal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><octamer-binding protein Oct-6><pathway><perinatal deaths><programs><promoter><promotor><protein function><pulmonary><resection><respiratory><respiratory dysfunction><respiratory function><sleep-related breathing disorder><social role><synapse><synaptic circuit><synaptic circuitry><transcription factor><transcription factor Oct-6><transcription factor tst-1><transcriptome sequencing><transcriptomic sequencing><vertebrata>