VALINA L. DAWSON
The brain is the most complex organ in the body and allows us to interact with the world around us. Unlike many other tissues, neurons are not routinely or easily replaced. When neurons are lost due to trauma or disease there is a significant loss of function. In order to treat patients suffering neurologic dysfunction it will be necessary to accomplish several integrated goals including: (1) understanding the cellular death signaling pathways to reveal potential drugable targets for pharmaceutical intervention, (2) understanding endogenous survival pathways to learn how to induce these pathways to provide complimentary or alternative therapeutic targets, (3) to learn how nerves regenerate and find their appropriate targets, (4) to restore full function it may be necessary to replace the neurons that have been lost.
Our neurotoxicity model focuses on ischemic (loss of glucose and oxygen) and excitotoxic injury. We have identified a highly choreographed signal cascade triggered by glutamate acting at the NMDA receptor, stimulating neuronal nitric oxide synthase that triggers lethal peroxynitrite generation and poly(ADP-ribose) polymerase activation. We have recently described a new interaction between nuclear activation of poly(ADP-ribose) polymerase and mitochondrial release of apoptosis inducing factor, in the integration of the death signal. Since this form of cell death is active in many organ systems we have named this process parthanatos to distinguish it from other forms of cell death such as apoptosis, necrosis, and autophagy. Current research is focused on understanding how the poly(ADP-ribose) polymer elicits signaling in the cytoplasm and at the mitochondria, how AIF is released from mitochondria and how AIF triggers DNA fragmentation and nuclear condensation.
CELL SURVIVAL - PRECONDITIONING
We also strive to understand survival signaling in the brain. We have undertaken gene discovery projects utilizing methods developed in the laboratory to identify the genes and proteins that are responsible for mediating the profound protection afforded to the brain by the phenomena of preconditioning. These screens have yielded a cornucopia of new survival proteins that have not previously been realized to participate in brain survival. We are currently characterizing these genes and proteins to better understand their biology as well as identify potential targets to develop new therapeutics to protect the brain. In addition we have learned new neurobiology.
Neural precursor or stem cells provide promise and hope that lost neurons can be replaced. However, many of these cells die before they integrate into the host. We have conducted a genetic screen using a siRNA library and have uncovered a collection of new cell death molecules. We are beginning to investigate these new death proteins in order to understand cell death programs in neural precursor, stem cells as well as the brain. These studies are integrated with ongoing investigations into neuronal death and survival pathways.
PARKINSON'S DISEASE - LRRK2
Parkinson’s disease (PD) is a complex neurodegenerative disorder that is both sporadic and familial. It is currently thought that PD results from a combination of environmental factors and genetic susceptibility. Gene mutations in the leucine-rich repeat kinase 2 (LRRK2) have recently been shown to result in autosomal dominant PD. A high prevalence of these mutations in unrelated PD patients strongly suggests that mutant LRRK2 may play a key role in sporadic PD as well. To understand the role of LRRK2 in the function and dysfunction of neurons we have generated LRRK2 knockout mice and LRRK2 transgenic mice to explore the actions of LRRK2 in the brain. In is likely that LRRK2 functions in large protein complexes and thus we are identify and characterize LRRK2 interacting proteins. The goals of this project are to identify and characterize the interaction of LRRK2 and its protein targets through state-of-the art protein biochemistry, including a collaboration with the HiT Center using the protein chip technology. We hope that these studies of LRRK2 may potentially lead to the development of novel therapeutic strategies for the treatment of PD.
STEM CELL PROJECTS
Botch is a novel protein discovered in the lab that regulates Notch signaling, an important pathway in the development of stem cells. We are studying Notch and Botch signaling in human neural precursor cells differentiated from human embryonic cells. Experiments are designed to understand how Botch and Notch signaling leads to differentiation and maturation into specific cells of the nervous system.
The ability to reprogram adult cells into stem cells called inducible pluripotent stem cells (iPS cells) allows the investigation of basic neurobiology in human neural cultures. We are using iPS cell cultures to generate neural cultures representative of the human cortex and/or striatum to explore the pathways involved in both neurotoxicity and in the enhanced neuroprotection afforded by preconditioning. The goal of this research is to better understand these signaling pathways in human neurons and to identify pharmaceutical agents that can protect human neurons from injury that may occur in setting such as stroke, trauma or neurodegenerative diseases such as Parkinson’s disease.