Project Details
Description
Abstract
Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are found in patients with
intellectual disabilities (ID) that show cognitive impairment ranging from mild (IQ 50-70) to severe (IQ < 30).
However, the molecular mechanisms by which KDM5 proteins impact neuronal development and function remain
unknown, leaving a large knowledge gap and preventing the identification of potential treatments for affected
patients. Thus, the long-term goal of our research is to define at the molecular level how KDM5 regulates gene
expression patterns necessary for neuronal development and function. We will achieve this using Drosophila
because it is an established model organism used to define the molecular basis of human neurodevelopmental
disorders. Studies described here use a powerful combination of genetic tools, cell biological analyses and
cognitive behavioral assays to dissect KDM5’s gene regulatory activities in neuronal cells at distinct stages of
development. In addition to classical loss of function analyses utilizing a newly generated kdm5 null allele and
cell type specific inducible RNAi-mediated knockdown assays, we have generated a set of eight fly strains, each
of which harbors a mutation in Drosophila kdm5 analogous to a human ID allele. This approach is possible
because all disease-associated mutations occur in evolutionarily conserved amino acids. Data generated using
these tools lead us to propose the central hypothesis that KDM5 regulates the expression of genes essential for
neuronal development and function, and that this is affected by missense mutations associated with intellectual
disability. This hypothesis will be tested in three specific aims. The first aim addresses the role of KDM5 in adult
brain function by defining the mechanism by which KDM5 activates ribosomal protein (Rp) genes, as de novo
translation has an evolutionarily conserved role in learning and memory. The second aim focusses on the role
of KDM5 during development by determining the mechanism by which KDM5 functions in larval neuronal stem
cells (neuroblasts) to facilitate the subsequent growth and guidance of the neurons required for learning and
memory. The third aim defines the temporal and spatial requirements of KDM5 for learning and memory. This
work is significant because we will define new mechanisms of gene regulation by KDM5 that are critical for
neuronal development and activity in addition to providing insight into the underlying causes of
neurodevelopmental disorders.
Status | Finished |
---|---|
Effective start/end date | 1/15/15 → 2/28/24 |
Funding
- National Institute of General Medical Sciences: $302,400.00
- National Institute of General Medical Sciences: $321,475.00
- National Institute of General Medical Sciences: $336,000.00
- National Institute of General Medical Sciences: $321,475.00
- National Institute of General Medical Sciences: $321,475.00
- National Institute of General Medical Sciences: $117,172.00
- National Institute of General Medical Sciences: $336,000.00
- National Institute of General Medical Sciences: $335,166.00
- National Institute of General Medical Sciences: $321,475.00
- National Institute of General Medical Sciences: $204,303.00
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