Uncovering the transcription factors that control human motor neuron cell fate
Active Project Grant Awarded Last action
- Award ID
- F30HD117663
- Recipient
-
New York University UEI M5SZJ6VHUHN8
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $217,036
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date 46% complete
- Place of performance
- New York, NY 10016, USA
Award details come from USAspending.gov.
Description
- Abstract
- To generate all the cell types that comprise the human body, pluripotent cells transition through various identities before reaching their terminal cell fates by relying on a tightly regulated series of gene expression profiles regulated by transcription factors (TFS). A comprehensive understanding of the critical regulator TFS driving cellular differentiation processes will facilitate the study of human developmental disorders and the generation of clinically relevant cell types for disease modeling and regeneration. Motor neurons (MNS) from the ventral spinal cord are a clinically relevant cell type and a classic neuronal developmental model. MNS are efferent neurons that act in circuits to innervate muscles, and impairment of MNS leads to muscle atrophy and eventual loss of motor function. MNS are the primary cell type implicated in spinal muscular atrophy (SMA), a developmental disorder, and amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, both of which affect nearly 1 in 10,000 people. Currently, the only available treatments for these diseases are supportive. Thus, my proposal aims to enhance our understanding of MN differentiation. The human genome codes for over 1600 TFS, but only about 50 TFS are known to be important during human spinal cord development. Recent scrna-SEQ analyses reveal that more than 800 TFS are differentially transcribed during this developmental process, suggesting that the field has under-sampled the TF landscape. As an unbiased approach to identify important TFS for differentiation processes, two crispr screens have uncovered previously unknown TFS important for neuronal cell fates. Using a simple, TF-directed neuronal differentiation system, the first screen revealed that ZBTB18, a C2H2 zinc finger repressor that binds e-box motifs, is critical for neuronal fate downstream of NEUROG2. In humans, ZBTB18 mutations are associated with nervous system developmental defects. ZBTB18 has also been predicted to be critical for the generation of spinal cord MNS. Using a small molecule-directed MN differentiation method in mouse embryonic stem cells, the second, unpublished screen revealed 69 new TF candidates essential for progression through the stages of the MN differentiation process. This proposal aims to further characterize the TFS from these two screens by addressing the following questions: 1. What is the role of ZBTB18 in human MN differentiation? 2. Which TFS identified by the mouse screen have conserved functions in human MN differentiation? The completion of this proposal will uncover a more complete gene regulatory network controlling human MN differentiation.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $55,114 | |
| Amendment | $53,974 | |
| Amendment | $0 | |
| Amendment | $53,974 | |
| Original award | $53,974 |
Quick answers
Who received award F30HD117663?
F30HD117663 was awarded to New York University by National Institute of Child Health and Human Development (National Institutes of Health) on June 20, 2025.
How much is award F30HD117663 worth?
$217,036 has been obligated on F30HD117663.
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