2009 — 2013 |
Noguchi, Kevin K |
K01Activity Code Description: For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
Glucocorticoid and Stress Induced Cerebellar Neural Progenitor Cell Apoptosis
DESCRIPTION (provided by applicant): There is considerable evidence that perinatal glucocorticoid (GC) exposure, either from the administration of drugs or during periods of extreme perinatal stress, can produce neurodevelopmental deficits leading to permanent neuropsychlatric disorders. In our preliminary results, we have found that acute injections of GCs and exposure to neonatal stress can both produce an identical pattern of neural progenitor cell (NFC) apoptotic degeneration in the developing rodent cerebellum. Therefore, delineating the underlying mechanisms for this toxicity has the potential to provide important information for perinatal healthcare and basic mechanisms of neuredevelopment. While the cerebellum has traditionally been associated with neuromotor function, recent research has established that it plays a critical role in cognitive and affective behaviors. Therefore, this research may also suggest a role for GC induced cerebellar dysfunction in a variety of neuropsychlatric conditions. Consistent with this idea, prematurely born infants exposed to GCs have been found to develop cognitive and neuromotor deficits when compared to a saline control group. Of equal importance, exposure to perinatal stress has been associated with cognitive and affective dysfunction and has been implicated in a variety of neuropsychlatric conditions. In Aim 1, the applicant will test the potential safener drug lithium for its ability to protect against GC induced NPC apoptosis and its long term effects in the cerebellum. In Aim 2, the applicant will determine whether a perinatal stress paradigm associated with increased corticosterone release can produce apoptosis in cerebellar NPCs acutely and produce long term reductions in cerebellar granule cells. Finally, in Aim 3, the applicant will make use of the Cre/lox recombination system to selectively knockout GC receptors in the NPCs of the cerebellum in order to determine their role in this toxicity and cerebellar development. While conducting the proposed research plan the applicant will become trained in several areas critical for his career development including immunohistochemistry, pharmacokinetics, electron microscopy, stereology, the use of both knockout mice and conditional knockout mice, radioimmunoassay, and viral vector maintenance and use. PUBLIC HEALTH RELEVANCE: Currently, a large number of fetuses/neonates are exposed to GCs for either perinatal medical treatment or during the endogenous release associated with perinatal stress. Both of these conditions are known to produce permanent behavioral deficits yet little is known about how this occurs. Therefore, this research may provide key insights on the effects of exposure to GCs on perinatal health.
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0.948 |
2015 — 2016 |
Noguchi, Kevin K |
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. |
Anesthesia Toxicity in Neonatal Primate Brain
DESCRIPTION (provided by applicant): A decade ago, the applicant and colleagues discovered that drugs that have either NMDA antagonist or GABAA agonist properties, a description that fits alcohol and all general anesthetics, trigger widespread death of nerve cells in the developing animal brain. In order to maximize the translational significance of our anesthesia toxicity studies, we applied for and were awarded a grant (start date Jan 2007) to study this phenomenon in the developing non-human primate (NHP) brain. The present application is a request for renewal of funding for ongoing studies pertaining to the apoptogenic properties of anesthetic drugs in the developing NHP brain. This work is being performed in collaboration with colleagues at Washington University and Oregon Health & Science University and Oregon National Primate Research Center. In the first 4 years of the grant period we have developed a valuable data base documenting susceptibility of the developing fetal and neonatal NHP brain to apoptotic death of brain cells (both neurons and oligodendrocytes) induced by clinically relevant exposure to each of three anesthetic drugs (isoflurane, ketamine, propofol). In this renewal application we are proposing to conduct additional NHP studies to further clarify the potential neurotoxicity of anesthetic drugs for the developing NHP brain and explore ways of modifying anesthesia protocols to enhance their safety for the developing brain. We have already developed a valuable data base, and now want to build upon that base toward the goal of achieving improved safety in the clinical application of anesthetic drugs in pediatric and obstetric medicine. The aims of the proposed research are to determine: 1) If there is a significant positive correlation between duration of anesthesia exposure and the number of neurons and/or oligodendrocytes that undergo apoptotic cell death; 2) How anesthesia without surgery compares in toxic impact with anesthesia with surgery; 3) How long into the post natal period does the brain remain vulnerable to significant neuronal or glial loss following clinically relevant exposure to anesthesia; and 4) Can the apoptotic response to anesthesia be prevented or significantly mitigated by adjunctive administration of neuroprotective drugs.
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0.948 |