Nuri Bradford Farber - US grants

DESCRIPTION (provided by applicant): This is a second revision of a previously submitted application (R01-ES012443-01). It has recently been shown that apoptotic neurodegeneration can be triggered in the in vivo developing rodent CNS by any of several classes of drugs that have in common the property of abnormally suppressing neuronal activity. The period of vulnerability coincides with synaptogenesis, also known as the brain growth spurt period, which occurs postnatally in rodents (first 2 weeks after birth) and both prenatally and postnatally in humans (third trimester and several years after birth). Included among the offending agents are drugs that block NMDA glutamate receptors, drug that hyperactivate GABAA receptors and ethanol, which has both NMDA antagonist and GABAmimetic properties. The apoptogenic action of ethanol is a promising candidate to explain the reduced brain mass and neurobehavioral disturbances associated with the human Fetal Alcohol Syndrome. While interference with NMDA and GABAA neurotransmission during synaptogenesis is putatively responsible for much of ethanol's neurotoxic action, other mechanisms may also be operative in that ethanol kills some populations of neurons that are not affected by NMDA antagonist or GABAmimetic drugs. The applicants have recently discovered that an ethanol-like neurodegenerative syndrome can be induced in the developing rodent brain by certain solvents that are widely used in the industrial world to facilitate the manufacturing process or to dissolve and/or add functionality to marketed products, including injectable drugs used in human medicine. For example, we have found that dimethyl sulfoxide (DMSO) and propylene glycol, which are widely used throughout the world and are generally considered having a very low toxicity potential, trigger a robust neurodegenerative reaction in the developing rodent brain. This is not a property of all solvents in that polyethylene glycol, a very widely used solvent, does not display such activity. The Aims of the proposed research are to more fully characterize the neurodegenerative reactions induced by DMSO and propylene glycol, to screen other solvents for their ability to mimic this type of neurodegenerative phenomenon, to evaluate the degree of risk associated with using these agents as solvent vehicles for drugs administered intravenously to human neonates and, by a combined in vivo/in vitro approach, attempt to elucidate mechanisms underlying these newly discovered neurotoxic phenomena.

[unreadable] DESCRIPTION (provided by applicant): This application requests support for studies pertaining to the principal investigator's recent finding that glucocorticoids (e.g., dexamethasone) trigger apoptosis in neural progenitor cells (NPCs) in the external granule layer of the cerebellum. Glucocorticoids induce the death of cerebellar NPCs only during a brief period when these cells are dividing and subdividing in order to produce neurons that will subsequently become granule cells in the internal granule layer and, possibly, interneurons in the molecular layer. In rodents this period occurs between postnatal days 4-10. In humans the corresponding period would last from the 20th week to the 45th week post conception. After cerebellar neurogenesis has been accomplished, the NPCs are removed by apoptosis. The signal that these NPCs use to decide when to begin to kill themselves by apoptosis is unknown. Determining what the signal might be has important implications for developmental neurobiology. The fact that 11[unreadable]-hydroxysteroid dehydrogenase type 2, an enzyme that breaks down only endogenous glucocorticoids, disappears from the external granule layer of the cerebellum at the end of neurogenesis period, when NPCs undergo apoptosis, suggests that endogenous glucocorticoids might be the natural signal. Clinically, exogenous glucocorticoids (e.g., dexamethasone, betamethasone) are given to mothers, who are at high risk of giving birth prior to 32 weeks gestation, in order to induce maturation of the fetal lungs. In addition postnatal premature infants receive corticosteroids for 2-42 days either to prevent or treat chronic lung disease. Follow-up data from clinical trials suggest that infants exposed to glucocorticoids in addition to having developmental delays and smaller brains and bodies, have impairments in motor skills, motor coordination, and visualmotor integration. These data have raised concern about the relative safety of glucocorticoid exposure in the human infants. The histological work proposed in Specific Aim 1 of this application seeks to determine that glucocorticoids produce apoptosis by activating glucocorticoid receptors and that endogenous glucocorticoids are less likely to produce this toxicity than synthetic ones. Then the long-term effect of a single dose of glucocorticoids on cerebellar neuronal numbers and on motor and coordination tasks will be studied in Specific Aim 2. Results of the proposed studies could provide immediate guidance on which glucocorticoids might be less toxic in humans. In addition the findings will serve as a basis for conducting future studies aimed at more fully understanding the basic biology underlying decisions about when cells undergo apoptosis, and on finding treatments that might be more effective in preventing this drug-induced apoptosis. [unreadable] [unreadable] [unreadable]

1,2-Propanediol; Alcohol, Methyl; Brain region; CRISP; Carbinol; Computer Retrieval of Information on Scientific Projects Database; DMSO; Demasorb; Demeso; Dimethyl Sulfoxide; Dimethylsulphinyl; Dimethylsulphoxide; Domoso; Dose; Dromisol; Funding; Grant; Human; Human, General; Infant; Institution; Investigators; Killings; Macrogols; Man (Taxonomy); Man, Modern; Methanol; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; Neurons; PEG; Polyethylene Glycols; Polyethylene Oxide; Polyethyleneoxide; Polyoxyethylenes; Propan-1,2-Diol; Propanediols; Propylene Glycols; Propylene glycol; Range; Research; Research Personnel; Research Resources; Researchers; Resources; Solvents; Source; Sulfinylbis(methane); United States National Institutes of Health; Wood Alcohol; brain tissue; neuronal

There is a growing demand for psychiatrists to conduct research in the areas of mental health and illness that is currently not being met, leading to multiple calls for enhancing research training during residency in order to increase the number of academic psychiatrists. To address this need for more clinician scientists, the General (Adult) Psychiatry and Child and Adolescent Psychiatry (CAP) Training Programs at Washington University propose to create the Psychiatry Residency Research Education Program (PRREP) that spans both training programs. PRREP seeks to increase the number of psychiatric residents and fellows who become successful academic psychiatrists by addressing several key areas ? recruitment, career counseling, and better preparation of trainees for formal research training at the T32 level. PRREP will build on the strong history of research and mentoring of our Department of Psychiatry at Washington University. The program will have two phases. Phase 1 covers the application/recruitment period and the first two years of residency training and Phase 2 covers the advanced years of training and transition into early post-residency research fellowships. Phase 1 is designed to increase the number of psychiatry trainees interested in a research career by enhancing recruitment and providing early education (career counseling/mentoring, didactics, seminars, on-line coursework) and introductory research experiences. Participants interested in continuing in the program will transition to Phase 2. Phase 2 will provide additional research education and participants will design and conduct a formal research project with the aid of a mentor so that the participants are better prepared for more formal research training at the T32 level. Total time spent in research will be 12 months for a resident in the 4- year Adult program and 13.5 months for a CAP resident who is in training for 5 years. The program is also structured to accommodate individuals with significant past research experience (e.g. MD/PhDs) as well as trainees who come to Washington University as a first year CAP fellow. There are additional evaluation and dissemination components to the program. The requested R25 funds will allow us to transform our efforts in preparing residents for a career in academic psychiatry. PRREP will change training that consisted of a short period of required research time in the last year of training into one that will include recruitment efforts, mentoring, restructured didactics, formal coursework, and research opportunities throughout residency training.