The Marenda Lab is focused on understanding the cellular and molecular mechanisms that control neural development and behavior, using the fruit fly Drosophila melanogaster as an in vivo model.  Though the lab focuses on developmental neurobiology, the Marenda Lab has also created a number of models of human diseases that affect cognition and neural development, including models of CHARGE syndrome, Hereditary Spastic Paraplegia, and Alzheimer’s disease. 

Epigenetic Chromatin Remodeling Factor Kismet. Implications in neural development and CHARGE Syndrome

*This research is currently funded by NSF Grant IOS-1256114. Previous funded included NIH/NCRR 1R21RR026074 and the Pennsylvania Department of Public Health, Commonwealth of Pennsylvania

Proper control of gene expression is critical for the normal development and function of the nervous system. Epigenetic mechanisms, such as chromatin remodeling, are key steps in gene regulation, and have emerged as important processes in neural development and function. We have identified the chromatin remodeling ATPase kismet (kis) as necessary for the development and function of glutamatertic neurons in vivo. We have shown that kis is required for axon pruning of mushroom body neurons (required for learning and memory) and for synaptic function in motor neurons (glutamatergic neurons in Drosophila). In mice, we have found that the homolog of kis (CHD7) co-localizes with the vesicular glutamate transporters 2 and 3 (VGLUT2/3) in hippocampal neurons. In humans, haploinsufficenicy for CHD7 is associated with CHARGE syndrome, a congenital disorder that affects the development of multiple organ systems, including (but not limited to) the eyes, ears, heart, and nervous system. In this project, we are currently carrying out experiments to determine the mechanism of kis function in Drosophila glutamatergic neurons, and will determine the effect of Chd7 deficiency on glutamatergic neurons in mice.

Developing in vivo tools to study Alzheimer's Disease pathology and using these tools for drug screening and efficacy.

Previous funding included NIH/NINDS, R01NS057295 and the Drexel University Human Cognition Enhancement Program

The average cost of bringing a novel drug to market is (conservatively) $1.8 billion, and requires approximately 13.5 years of development. High throughput cell-based screening assays for drug discovery are very effective for identifying novel compounds that have the potential for therapeutic use. However, the effects of drugs on an organism often can not be accurately predicted by in vitro studies alone. In fact, one of the principal reasons for the high costs of drug development is due to the failure of candidate compounds in the initial in vivo efficacy and toxicity testing stages. Thus, if we can develop a rapid and sensitive in vivo test for drug efficacy and toxicity, we could dramatically increase the success rate and hopefully speed the effective drugs to the market. To this end, we have developed two novel in vivo models of AD using the fruit fly Drosophila melanogaster. One model expressing the human APP and human BACE genes in the central nervous system, while the second expresses the human APP, human BACE, and human Tau genes in the central nervous system. We have shown through biochemical, neuroanatomical, and behavioral analysis that these flies exhibit clinical AD neuropathology and symptoms. These include the generation of Aβ40 and Aβ42, the presence of amyloid plaques, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. These phenotypes are generated very rapidly for an in vivo system. All of these phenotypes are present within the first few days of adult fly life, which is roughly 2 weeks in total from embryogenesis to adult. Treatment with a gamma-secretase inhibitor, as well as other pharmaceutical agents shown to have a neuroprotective effect in cell culture have suppressed these phenotypes, suggesting that our model could be used as a sensitive in vivo predictor of drug efficacy for preclinical analysis. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification and validation of AD therapeutic interventions rapidly and in vivo. We are currently performing an initial drug screen with these models, and will follow up on the hits we get from this screen in mouse models of AD.