Role of HP1Β-mediated heterochromatin organization in neurodevelopmental disorders: CBX1-related syndrome as a model
Active Project Grant Awarded Last action
- Award ID
- K02NS140483
- Recipient
-
The University Of Texas Southwestern Medical Center UEI YZJ6DKPM4W63
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $529,200
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 35% complete
- Place of performance
- Dallas, TX 75390, USA
Award details come from USAspending.gov.
Description
- Abstract
- An increasing number of neurodevelopmental disorders are causally linked to variants in genes encoding chromatin proteins that regulate heterochromatin, transcriptionally silenced genomic regions. We recently discovered one such diagnosis, CBX1-related syndrome, characterized by developmental disabilities, hypotonia, and autistic features. This syndrome is caused by heterozygous variants in the CBX1 gene, which encodes heterochromatin protein 1 beta (HP1Β), a core structural protein of heterochromatin. The patient-identified variants are all missense within a genomic region encoding a known functional domain of HP1Β. The molecular mechanism of CBX1-related syndrome remains to be determined, although our previous publication suggested dominant-negative effects of the mutant HP1Β. The predominance of neurological manifestations in individuals with CBX1 variants suggests the important role of HP1Β in neuronal gene regulation, but the function of HP1Β in brain tissue remains elusive. To investigate the mechanisms underlying CBX1-related syndrome, we created mouse lines with patient-identified CBX1 variants. Heterozygous CBX1 mutant mice show behavioral abnormalities that suggest delayed neurotransmission. RNA sequencing of CBX1 mutant mouse brain tissue revealed increased expression of genes regulating synaptic function. These models and preliminary data provide an opportunity to explore the mechanisms linking CBX1 variants to neuropathology. The overall objective of this study is to elucidate the mechanisms of HP1Β-mediated heterochromatin regulation and the impact of patient- identified CBX1 variants in mouse models of CBX1-related syndrome. The rationale for this project is that elucidating the impact of the patient-identified CBX1 variants will pave the way toward identifying potential therapeutic approaches for CBX1-related syndrome, because elimination of mutant HP1Β could ameliorate cellular dysfunction if its effects were dominant-negative. The central hypothesis is that HP1Β variants seen in human patients interfere with neurodevelopment by increasing expression of genes within heterochromatin through a dominant-negative mechanism. This hypothesis will be tested by comparing transcriptomic/epigenomic and neurobehavioral phenotypes among mice with CBX1 missense and loss-of- function variants and wild-type mice. The knowledge gained from the proposed studies will have a positive impact on the molecular mechanistic understanding of not only CBX1-related syndrome but also neurodevelopmental disorders caused by heterochromatin dysfunction in general. This work will enable me to obtain training in utilizing mouse models of neurodevelopmental disorders, in collaboration with leading experts. The completion of this project will provide me with the skills and experimental data required for an R01 application. The training available through this K02 award represents an essential component toward the attainment of my long-term goal of studying the molecular mechanisms underlying the neurodevelopmental symptoms seen in CBX1-related syndrome and other neurodevelopmental disorders caused by heterochromatin dysfunction.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $264,600 | |
| Original award | $264,600 |
Quick answers
Who received award K02NS140483?
K02NS140483 was awarded to The University Of Texas Southwestern Medical Center by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on February 1, 2025.
How much is award K02NS140483 worth?
$529,200 has been obligated on K02NS140483.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award