Eric Turner - US grants

bioimaging /biomedical imaging; technology /technique development

This application is an integral part of a career commitment by the applicant to understand how the diverse types of neurons found in the mammalian nervous system are generated and maintained throughout life. We currently study DNA-binding transcription factors that serve as switching molecules in the nervous system, specifically Brn-3.0, described extensively in our previous work, indicates a role in the terminal differentiation and maintenance of specific neurons in the CNS and peripheral sensory system. Unlike many transcription factors expressed in development, Brn-3.0 persists into adulthood but its role in the mature brain is unknown. We have also cloned and paretically characterized regulatory elements in Brn-3.0 genomic locus. Work elsewhere has shown that targeted disruption of Brn-3.0 in mice results in neonatal death and loss of neurons in the sensory ganglia and some CNS nuclei which express this factor. One model for this neuronal loss is a failure of Brn-3.0(-/-) neurons to respond to neurotrophins which are necessary for survival. The Specific Aims of this application are: (1) Specifically express an axonal marker protein, tau-beta-gal, by homogous recombination at the Brn-3.0 gene locus ("knock-in"), allowing the normal axonal projections of the Brn-3.0 neurons to be traced in tau-beta-gal heterozygous mice. (2) Examine homozygous tau-beta-gal expressing animals which are null mutants for Brn-3.0 to allow determination of the extent of development and axonal projection of these neurons prior to cell death. (3) Examine the expression of Brn-3.0 message and protein, including the number of Brn-3.0 expressing neurons and magnitude of Brn-3.0 expression, in mature and senescent mice.

DESCRIPTION (Adapted from applicant's abstract): This NIMH Career Development (K02) proposal is an integral part of a commitment by the applicant to discover fundamental mechanisms of brain development and to ultimately apply these basic principles to understanding psychiatric illnesses which have a genetic or developmental component. The candidate holds a B.S. in biology from Stanford University, following which he completed M.D.-Ph.D. training through the NIH-sponsored MST Program at the University of Washington, with a Ph.D. in biochemistry for developmental research in marine invertebrates. He then completed residency training in psychiatry at the University of California, San Diego, and is a board-certified psychiatrist. After clinical training, he assumed research as a Physician Fellow of the Howard Hughes Institute at the University of California, San Diego, where his work led to the discovery and characterization of novel regulatory genes expressed in the brain. Since 1994, he has continued research in this area as a member of the faculty of the Department of Psychiatry, University of California, San Diego, and a member of the University of California, San Diego interdepartmental Program in Neurosciences. The candidate is now an independent investigator, whose fully equipped and funded laboratory has produced several published reports. The candidate's home department is extremely supportive of this research program, and the research environment in neuroscience at University of California, San Diego and affiliated institutions is among the best in the nation. The candidate has been engaged in studies of the neural transcription factor Brn-3.0 and related POU-domain factors expressed in the developing brain. The expression pattern of Brn-3.0 indicates a role in the terminal differentiation of specific neurons in the CNS and peripheral sensory system. However, the expression of Brn-3.0 in the CNS suggests that it is a downstream target of certain neuroepithelial patterning genes. Understanding the factors which regulate developmental expression of Brn-3.0 combined with knowledge of how Brn-3.0 controls downstream target genes will define a developmental pathway for the Brn-3.0-expressing neurons. The experiments proposed here include three complementary sets of experiments which will elucidate the neurodevelopmental pathway of the Brn-3.0-expressing neurons: (1) Investigate the role of Pax-3 as an upstream regulator of Brn-3.0 expression in Pax-deficient mice and by ectopic expression of Pax-3 in developing embryos. (2) Further define regulatory elements in the Brn-3.0 gene locus in transgenic mice. (3) Compare the functional DNA recognition sites of Brn-3.0 to those of other POU proteins expressed in the brain to begin to decipher the transcriptional genetic code of the nervous system.

DESCRIPTION (Provided by applicant): The University of California, San Diego (UCSD) Fellowship in Clinical Psychopharmacology and Psychobiology is a highly productive program for the training of research-oriented psychiatrists, psychologists and behavioral neuroscientists. This program has taken optimal advantage of active research faculty in the Department of Psychiatry and produced, over nearly two decades of training, multiple outstanding clinician-scientist psychiatric researchers such as Drs. S. Craig Risch, Robert Gemer, John Lisansky, William Byerley, Barbara Parry, John Kelsoe, Neal Swerdlow, and Frederick Moeller. The diverse and active research programs in the Department of Psychiatry at UCSD allow for a superb combination of one-on-one supervision of research fellows by very active and highly productive supervisors, a series of closely supervised clinical and laboratory research rotations, and an ever-evolving series of didactic research educational experiences. These training opportunities along with implementation of a scientific review process of the fellows? research progress by senior basic and clinical scientists of the UCSD Department of Psychiatry optimize the ability of research trainees to achieve discrete and measurable goals throughout fellowship training. The strengths of our nationally recruited trainees coupled with assets of the training faculty combine to facilitate the production of research as measured by applications to human or animal research subjects committees, presentations at national and international meetings, publication of research articles, submission of grant applications and successful competition for research funds. The majority of graduates from this program successfully continue research training and many have obtained independent funding and accepted positions as faculty to emerge as outstanding independent investigators with tenure in research oriented departments.

DESCRIPTION (provided by applicant): This proposal requests continued NIMH funding for the University of California, San Diego "Fellowship in Biological Psychiatry and Neuroscience", T32-MH18399. This program represents a long tradition in mental health research training at UCSD. The success of the program is demonstrated by the remarkable productivity of its trainees in terms of publications, major awards, and subsequent funding. In the most recent project period alone, trainees have received five NARSAD Young Investigator awards, three NIH K-series training grants, and several other national prizes. Furthermore, all recent program graduates have published first-authored peer-reviewed research papers reporting their Fellowship work, and nearly all continue to work in full-time academic research positions. The need for training programs of this kind is profound. Both the scientific community and the informed public hope and expect that major recent advances in basic neuroscience and genetics, such as functional imaging of the living human brain and the genome project, will lead to breakthroughs in the understanding and treatment of mental disorders. However, complex research technologies take years of training to master, and a lack of researchers who can use these methods to understand the etiology of psychiatric disorders, and transform basic findings into new therapies, could prevent their potential from being realized. Especially problematic is a lack of clinician-scientists who have the training necessary to work at the forefront of biological psychiatry and also translate scientific achievements into new treatments. In the coming project period, the specific goals of the program are: 1) Maintain and improve both the ethnic and the academic diversity of the program trainees using specific recruitment strategies. 2) Foster innovation by promoting exchange between a dynamic mix of psychiatric physicians, clinical psychologists and basic neuroscientists. 3) Provide systematic oversight of mentor assignments, research projects, and trainee progress beginning prior to program entry and continuing throughout training. 4) Provide a strong core of research didactics, yet tailor requirements to meet the specific needs of each trainee. 5) Provide continual education and mentorship in career development "survival skills" which will foster the trainees'transitions to independent research careers.