Deregulation of apoptosis can lead to neuronal loss and degeneration as seen in many neurological disorders such as Alzheimer's and Parkinson's disease. In order to effectively treat these diseases, it is important that we understand the mechanisms of cell death and how they contribute to human pathologies. Apoptosis functions through the apoptosome, a highly conserved molecular machine that controls caspase activation. The broad evolutionary conservation among metazoans permits us to take advantage of powerful genetic models to dissect the underlying function and regulation of the apoptosome. Because Drosophila is an exceptionally sophisticated model for both genetics and neurobiology, we can rigorously study the function of putative regulators of the apoptosome in neuronal development and neuronal pathologies. In flies, mutants of the apoptosome components, dark and drone, show distinct neuronal phenotypes that are manifestations of defective cell death. Using these phenotypes, we initiated a screen for conserved regulators and effectors of the apoptosome. The rationale for this initiative hinges on the unique phenotypes associated with loss-of-function mutations in dark and drone to identify putative regulators and effectors of the apoptosome. Over twenty cell death defective mutations that phenocopy dark and drone were recovered. Included among these is an allele of Homeodomain Interacting Protein Kinase (HIPK). Through unknown mechanisms, the mouse counterparts of this gene specify proper development of the nervous system and are implicated in the regulation of neuronal cell death. Through the use of novel null alleles at the HIPK locus, we have shown that HIPK is an important regulator of cell death in the developing animal and in the nervous system.
My first aim will work to 1) determine where HIPK functions relative to known apoptotic players with epistasis studies, 2) further our understanding of the mechanism of HIPK action with respect to the apoptosome, and 3) place the action of HIPK in canonical signaling networks including Dorsal/NFKB.
My second aim addresses an additional PCD defective mutation, pcdnI2, isolated from our screen but not yet implicated in cell death. By generating a novel null allele of pcdnI2, I will determine whether the implicated locus, CG31522, is responsible for cell death defective phenotypes, describe its role in developmental and neuronal cell death, and place its action relative to known members of the apoptotic pathway.
Apoptosis is a key component of many neurological disorders. Understanding apoptotic mechanisms will aid in treatment and understanding of these conditions. ? ?
| Link, Nichole; Kurtz, Paula; O'Neal, Melissa et al. (2013) A p53 enhancer region regulates target genes through chromatin conformations in cis and in trans. Genes Dev 27:2433-8 |
