2007 — 2011 |
Margeta, Marta |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
The Role of Atp-Sensitive Potassium Channels in Neurodegeneration @ University of California San Francisco
DESCRIPTION (provided by applicant): Project Summary. This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Marta Margeta for a role of an independent investigator. The principal guidance will be provided by the project sponsor, Dr. Lily Jan, who is an internationally recognized expert on ion channel biology and has a distinguished record of training independent scientists. The project co-sponsor, Dr. Stephen DeArmond, an expert in the pathology of neurodegenerative diseases) and members of the advisory committee will provide additional guidance. The research program will address the hypothesis that ATP-sensitive K+ (KATP) channels, which link the metabolic state of the cell to its electrical activity, play a role in the pathogenesis of Parkinson's disease (PD). Activation of KATP channels protects catecholaminergic cells in culture against rotenone- and MPP+-induced cell death. In addition, the sensitivity of substantia nigra dopaminergic neurons to certain forms of neurodegeneration depends on the KATP channel subtype they express. In this project, the role of KATP channels in dopaminergic neurodegeneration will be assessed through three Specific Aims. First, we will examine the expression pattern of KATP channel subunits in the human substantia nigra using autopsy-derived tissue from people with and without PD. Second, we will determine which forms of cell death are attenuated by KATP channel activation and which KATP channel subtype mediates the protective effect. Third, we will determine whether neurotransmitter-induced internalization of KATP channels abolishes their ability to attenuate cell death. The research training will be complemented by a formal didactic program in research ethics, genetics and advanced molecular techniques. The UCSF Pathology Department is fully committed to Dr. Margeta's career development. It provides an ideal setting for training of independent physician scientists by fostering interdisciplinary and interdepartmental collaborations and encouraging the creation of individually customized career plans. Relevance: PD is the second most common neurodegenerative disease, affecting 1-1.5 million of people in the United States. Despite recent major advances, the cause of sporadic form of PD is still unknown. The research proposed in this project will yield important insight into the pathogenesis of PD and potentially aid in development of new treatments for PD and other neurodegenerative diseases.
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2011 — 2015 |
Margeta, Marta |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Neuron-Glia Interactions in Regulation of Activity-Dependent Signaling Pathways @ University of California, San Francisco
DESCRIPTION (provided by applicant): Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases and stroke. However, low levels of reactive oxygen species (ROS) function as second messengers in many neuronal signal transduction pathways, which could thus be affected either by the disease process itself or by activation of endogenous antioxidant responses. The long term goal of this research is to define how endogenous antioxidant signaling regulates synaptic transmission and thus shapes vulnerability of synaptic networks to oxidative stress. The specific objective of this application is to elucidate molecular mechanisms underlying synaptic function of Nrf2, the transcriptional regulator of inducible antioxidant response that is a key determinant of neuronal susceptibility to injury. Our central hypothesis is that astrocytes respond to neuronal activity by enhancing current flow through ROS-sensitive glutamatergic NMDA receptors (NMDARs, the key mediators of both synaptic plasticity and glutamate excitotoxicity), while simultaneously activating Nrf2 pathway to protect neurons from ROS-induced damage and neurotoxicity. This hypothesis was formulated on the basis of the strong preliminary data obtained in our laboratory and will be tested by pursuing four specific aims. First, we will elucidate the molecular mechanism that underlies activity-mediated induction of Nrf2 pathway in neuron-astrocyte co-cultures. Second, we will establish whether neuroprotection induced by synaptic activity is enhanced when neurons are co-cultured with astrocytes. Third, we will determine how glial cells increase neuronal NMDAR current density in the mixed neuron-glia environment. Fourth, we will dissect the neuron-glia signal transduction cascade that underlies Nrf2-mediated regulation of NMDAR signaling and determine the effect of Nrf2 pathway activation on circuit plasticity. These aims will be accomplished through a combination of molecular, biochemical, electrophysiological, cell biological, and toxicological approaches whose feasibility in our hands has been established through the preliminary data;to dissect the roles of individual cell types, we will use primary neuronal, glial, and mixed hippocampal cultures, as well as neuron-glia co-cultures of defined cellular composition. The overall approach takes the field in a new direction by focusing on the role of neuron- glia interactions in the regulation and function of Nrf2 signaling in the brain, an aspect of Nrf2 biology that has not yet been investigated. Completion of the proposed research is expected to advance our understanding of ROS signaling and Nrf2 physiology in the brain;ultimately, such knowledge will enable development of pharmacologic treatments capable of harnessing neuroprotective power of endogenous antioxidants without negatively affecting neuronal activity and synaptic signaling. PUBLIC HEALTH RELEVANCE: By advancing our understanding of Nrf2 pathway biology in the brain, the proposed research will uncover optimal molecular and cellular targets for prevention and/or treatment of Alzheimer disease and other neurologic disorders with impaired synaptic plasticity. Thus, it is aligned with the NIH mission to foster fundamental scientific discoveries and innovative research strategies that form a basis for protection and improvement of public health.
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