1987 — 2002 |
Braff, David L. |
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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Sensory Gating and Habituation in Schizophrenia @ University of California San Diego
Attentional and information processing deficits have frequently been implicated in the psychopathology of schizophrenia. In recent years, the hypothesis of dopamine (DA) overactivity has also assumed significance in understanding schizophrenia. This proposal specifically outlines studies with humans and related animal models that will extend our knowledge of how DA overactivity relates to the sensory gating and habituation deficits that may underlie the cognitive fragmentation and thought disorder characteristic of schizophrenia. In animal experiments, we will further explore dopaminergic, noradrenergic, and specific anatomical pathways involved in the observed sensory gating deficits. To accomplish these goals, we propose to utilize the prepulse inhibition (PPI) and habituation of the startle reaction in humans and rats using the very similar paradigms, stimulus parameters, dependent measures, and statistical analyses that we have developed in our previous work. In humans, we will use electromyographic monitoring of the blink reflex component of the startle reaction (SR). In rats, we will use measures of whole body startle. Sensory gating will be accomplished by weak prestimulation and habituation using 121-trial tests in both humans and animals. Schizophrenic and control patients will be tested longitudinally and through various phases of their illness, while their clinical, symptomatic, neuropsychological, homovanillic acid levels, radioreceptor assay levels, and other measures are obtained. As an animal model of DA overactivity, rats having 6-hydroxydopamine-induced depletions of nucleus accumbens DA will be tested in the PPI paradigm following systemic treatments with apomorphine, noradrenergic agonists, and/or various dopaminergic antagonists. Liquid chromatography will be used to confirm the DA depletions. Our objectives are to clarify the neurochemical and anatomical pathways that underlie sensory gating and habituation deficits in schizophrenia and to explore the functional importance of dopamine overactivity in schizophrenia. We intend to further our understanding of how DA overactivity and its underlying neuroanatomic correlates may relate to the specific cognitive dysfunction, symptoms, and outcome of the schizophrenic disorders.
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0.958 |
1990 — 1992 |
Braff, David L. |
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. |
Sensory Gating &Habituation in Schizophrenia @ University of California San Diego
Attentional and information processing deficits have frequently been implicated in the psychopathology of schizophrenia. In recent years, the hypothesis of dopamine (DA) overactivity has also assumed significance in understanding schizophrenia. This proposal specifically outlines studies with humans and related animal models that will extend our knowledge of how DA overactivity relates to the sensory gating and habituation deficits that may underlie the cognitive fragmentation and thought disorder characteristic of schizophrenia. In animal experiments, we will further explore dopaminergic, noradrenergic, and specific anatomical pathways involved in the observed sensory gating deficits. To accomplish these goals, we propose to utilize the prepulse inhibition (PPI) and habituation of the startle reaction in humans and rats using the very similar paradigms, stimulus parameters, dependent measures, and statistical analyses that we have developed in our previous work. In humans, we will use electromyographic monitoring of the blink reflex component of the startle reaction (SR). In rats, we will use measures of whole body startle. Sensory gating will be accomplished by weak prestimulation and habituation using 121-trial tests in both humans and animals. Schizophrenic and control patients will be tested longitudinally and through various phases of their illness, while their clinical, symptomatic, neuropsychological, homovanillic acid levels, radioreceptor assay levels, and other measures are obtained. As an animal model of DA overactivity, rats having 6-hydroxydopamine-induced depletions of nucleus accumbens DA will be tested in the PPI paradigm following systemic treatments with apomorphine, noradrenergic agonists, and/or various dopaminergic antagonists. Liquid chromatography will be used to confirm the DA depletions. Our objectives are to clarify the neurochemical and anatomical pathways that underlie sensory gating and habituation deficits in schizophrenia and to explore the functional importance of dopamine overactivity in schizophrenia. We intend to further our understanding of how DA overactivity and its underlying neuroanatomic correlates may relate to the specific cognitive dysfunction, symptoms, and outcome of the schizophrenic disorders.
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0.958 |
1996 — 2001 |
Braff, David L |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Core--Psychophysiology @ University of California San Diego
Psychophysiological deficits are important in understanding both schizophrenia and the aging process. The Psychophysiology Core is designed to provide a multi-factorial assessment of several important domains of psychophysiological, information processing and attentional functions of subjects in the CRC. This Core is an extension of the Motor Function Core which has been productively in place during the past three years of the CRC's existence. The newly expanded Psychophysiology Core test battery reflects our growing awareness of the central role of psychomotor, attentional, and information processing deficits in understanding the schizophrenia and other psychotic disorders in general and late-life psychoses in particular. The Psychophysiology Core will provide an initial comprehensive battery which assesses eight measures from four domains of psychophysiological function including: motor function, startle plasticity, pupillometry and cerebral event-related potentials. Schizophrenia patients have been found to have deficits in all four domains and these deficits are related to the symptoms, course, and outcome of schizophrenia. In addition, these psychophysiological measures have been related to specific neural substrates that may be impaired in psychosis. The Psychophysiology Core will serve as a data acquisition and hypothesis testing module of the CRC. Since psychophysiological deficits across all of the four domains are associated with both schizophrenia and aging, this database will support the CRC themes of examining late-life psychosis cross-sectionally and longitudinally, and will add to our knowledge of treatment effects and predictors. The Psychophysiology Core will test formal hypotheses pertaining to the four Center-wide themes: (1) age of onset of schizophrenia; (2) different late-onset psychoses; (3) clinical outcome; and (4) treatment outcome, and in doing so will be able to address the following specific questions: (1) How does age of onset treated as a continuous variable correlate with deficits on psychophysiologic dependent measures in schizophrenia? (2) What psychophysiological deficits are observed across different late-onset psychoses? (3) What psychophysiological deficits are observed cross sectionally at baseline in patients who represent a variety of outcomes? and (4) Do the psychophysiological measures on admission to the treatment protocols predict or correlate with the subsequent treatment responses? In addition, the eight dependent measures of the Psychophysiology Core will be utilized to answer questions about cross-Core hypotheses relating to how these psychophysiological measures relate to specific deficits in clinical state, neuropsychological function, and brain imaging abnormalities. Finally, specific psychophysiological measures that appear to tap into similar processes and neural substrates will be correlated with each other. Via this cumulative effort, the significance of psychophysiological information processing and attentional abnormalities in late-life psychosis will be defined and clarified.
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0.958 |
2003 — 2009 |
Braff, David L. |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. 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. |
Gating and Inhibition in Schizophrenia @ University of California San Diego
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To identify subgroups of schizophrenia patients based on the convergence and divergence of the 4 inhibitory measures (PPI, P50 suppression, startle habituation, and the antisaccade task).
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0.958 |
2003 — 2007 |
Braff, David L. |
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. |
The Genetics of Endophenotypes and Schizophrenia @ University of California San Diego
[unreadable] DESCRIPTION (provided by applicant): [unreadable] Neurobiological deficits that serve as informative endophenotype markers have been demonstrated in schizophrenia by a number of different paradigms. Neurophysiological deficits are prominent in P50 event related suppression, prepulse inhibition (PPI) of the startle response, and the antisaccade (AS) task for eye movement dysfunction. Neurocognitive deficits in schizophrenia are revealed by poor performance on the CPT, verbal memory, and tests of working memory. Each of these deficits has also been demonstrated in clinically unaffected relatives of schizophrenia patients, which is evidence that they may reflect part of the heritable risk for the illness. This conclusion is reinforced by findings of deficits in non-psychotic, unmedicated schizophrenia patients, and schizotypal patients. The null hypothesis is that all 6 deficits reflect a single, common underlying heritable dysfunction in all schizophrenia patients. A test of that hypothesis requires measurement of all of these deficits in the same group of schizophrenia patient probands and their relatives. If they are all manifestations of the same genetic dysfunction (although perhaps expressed in different brain areas), then a multivariate analysis would show that they all contribute to a single dimension in both relatives and schizophrenia patients. An alternative hypothesis is that only one or a small subset of deficits is present in each family, which is consistent with the heterogeneity found in current genetic linkage studies. In that case, the multivariate analysis would show the different measures or subsets of them loading onto different dimensions. Schizophrenia itself is likely to be the result of multiple deficits in any individual. Therefore, the analysis is performed in the same cohort of schizophrenia patient probands and their relatives to take advantage of Mendel's second law, which holds that genetically independent deficits segregate independently. Hence, although schizophrenia patient probands themselves have multiple deficits, if the deficits are caused by different genetic factors, then they will segregate to different groups of relatives. This 7 site collaborative RO1 project will gather a combined total of 420 pedigrees (1680 subjects) and 525 normal subjects over 5 years (each site will contribute 1/7th of these totals). Findings of heritable deficits in specific measures will be used to guide the next generation of studies of the genetics of schizophrenia. [unreadable] [unreadable]
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0.958 |
2005 — 2009 |
Braff, David L. |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Consortium On the Genetics of Endophenotypes and Schizophrenia @ University of California San Diego
This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. To ascertain a minimum of 420 pedigrees from 7 sites (Harvard University, the Mount Sinai School of Medicine, UCLA, UCSD, UCHSC, the University of Pennsylvania, and the University of Washington) and 5 years of the project with a proband who has schizopherenia, by DSM-IV criteria. There must always be at least one parent and one other sibling in the pedigree (although the projected average pedigree size will be 4). To obtain the following robust and quality assured phenotype measures in this sample, in addition to a structures (DIGS) diagnosi: P50 suppression, prepulse inhibition of acoustic startle, antisaccade, continuous performance test, verbal memory, and working memory. To perform complex segregation analyses to determine which of these variables (a) are likely to reflect the same underlying neuronal processes, and (b) indicate genetic transmission of risk for schizophrenia. To perform a genome scan with polymorphic markers to assess the presence of genetic linkage of phenotypes identified in specific Aim 3 to specific chromosomal loci. Based on the data from specific aim 4, to model the neurobiological basis of risk for schizophrenia, as a combination of specific elements of genetically or non-genetically determined brain dysfunction.
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0.958 |
2008 — 2012 |
Braff, David L. |
U01Activity 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. |
5/5: a Genome-Wide Methylation Scan For Epigenetic Contributions to Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families and is the subject of intensive genetic studies. The study of epigenetic variation is an essential complement to conventional genetic disease studies, since the phenotypic consequence of DNA sequence depends on its epigenetic context. Unlike sequence variation, epigenetic marks, i.e. chemical modifications of DNA and associated proteins, are affected by age and the environment, providing an important link between the genetic predisposition to disease and crucially important risks related to lifetime epigenetic exposures. The importance of epigenetic marks in cancer is well established, and the relevance to neuropsychiatric disease is now emerging. An epigenetic contribution to schizophrenia (SZ) is supported by important, but often ignored discordance among MZ twins, the effects of DNA methylation (DNAm) precursors on psychotic symptoms in SZ, and evidence for DNAm variation in SZ candidate genes. While genome-wide association studies are ongoing for SZ, no similar effort has yet been pursued to identify epigenetic changes, largely due to technology limitations. Here we propose to determine the potential epigenetic contribution to SZ by combining robust experimental and statistical genome-wide methods for DNAm analysis recently developed by the applicants, with three large and well-characterized Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies. Our specific aims are: (1) Compare genome-wide methylation scan (GWMs) measures between SZ cases and controls using 1000 SZ cases / 1000 age/sex frequency matched control lymphocyte DNA as well as 140 SZ / 140 control brains; (2) Replicate GWM findings at 9,880 CpG sites in an independent sample of 2000 cases / 2000 controls from the NIMH Genetics Repository and fine-map the DNAm and examine expression patterns for the top 50 gene candidates; and (3) Integrate these epigenetic discoveries with the genetic data already being collected on these samples. These studies will provide the first comprehensive evaluation of the epigenetics of SZ and provide an unprecedented complement to SZ genetics data, allowing integration of genetic, environmental, and epigenetic effects on SZ. From an important treatment perspective, since epigenetic changes are potentially reversible, these studies may also lead to exciting new avenues for SZ therapy. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies. The study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies; unlike sequence variation, epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome- wide approach to the epigenetics of SZ, bringing to bear state of the art experimental and statistical approaches to the analysis of DNA methylation on a sample set identified and assessed by an outstanding network of SZ phenotypic experts working together in a highly collaborative manner.
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0.958 |
2009 — 2012 |
Braff, David L. |
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. |
4/4-a Genomic Approach to Schizophrenia @ University of California San Diego
Our goal is to identify genes that are enriched for rare or de novo genomic deletions or duplications in persons with schizophrenia and to determine the functional consequences of these mutations. Structural genomic variants are important causes of human genetic variation and are increasingly implicated in human disease. We have shown that rare deletions and duplications that impact genes are significantly more frequent among individuals with schizophrenia than among controls. These mutations disproportionately affect genes involved with neural development. Other investigators have shown that de novo structural mutations are 8-fold more frequent among individuals with sporadic schizophrenia compared to controls. Using a gene-based design, we propose to identify genes that are disproportionately altered by structural mutations in persons with schizophrenia. We anticipate that a gene important to schizophrenia will harbor different disease-causing mutations in different affected individuals (Aim 1). We also will identify genes with de novo structural mutations in patients with sporadic schizophrenia (Aim 2). The consequences of structural mutations in the most significant candidate genes will be characterized experimentally to determine the impacts of mutations on gene function (Aim 3). Cases have been assessed and sampled by four NIMH projects. These projects together have enrolled 1155 probands, 259 affected relatives, and 2965 unaffected relatives, including 431 proband-parent trios. Controls will be drawn from >3000 unrelated unaffected persons age >30 years from NIMH distribution 5. All cases and controls will be screened identically genome-wide with NimbleGen 2.1-million feature HD2 arrays, which can detect deletions and duplications as small as 3kb. Screening of the NIMH controls is supported by independent funds. If successful, our approach will identify multiple genes important for schizophrenia. Each of these genes should stimulate future efforts to develop more effective treatment and prevention strategies.
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0.958 |
2009 — 2010 |
Braff, David L. |
RC2Activity Code Description: To support high impact ideas that may lay the foundation for new fields of investigation; accelerate breakthroughs; stimulate early and applied research on cutting-edge technologies; foster new approaches to improve the interactions among multi- and interdisciplinary research teams; or, advance the research enterprise in a way that could stimulate future growth and investments and advance public health and health care delivery. This activity code could support either a specific research question or propose the creation of a unique infrastructure/resource designed to accelerate scientific progress in the future. |
5/5:Family-Based Genome-Wide Methylation Scan in Neurocognition and Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): Schizophrenia is a common profoundly disabling disorder that carries a heavy burden for patients and families and is the subject of intensive genetic studies. The study of epigenetic variation is an essential complement to conventional genetic disease studies, since the phenotypic consequence of DNA sequence depends on its epigenetic context. Unlike sequence variation, epigenetic marks, i.e. chemical modifications of DNA and associated proteins, are affected by age and the environment, providing an important link between the genetic predisposition to disease and crucially important risks related to lifetime epigenetic exposures. The importance of epigenetic marks in cancer is well established, and the relevance to neuropsychiatric disease is now emerging. An epigenetic contribution to schizophrenia (SZ) is supported by important, but often ignored discordance among MZ twins, the effects of DNA methylation (DNAm) precursors on psychotic symptoms in SZ, and evidence for DNAm variation in SZ candidate genes. This coordinated application builds on a strong foundation of an existing collaboration between six groups of investigators, with an already established and funded infrastructure, without which this research would not be possible. We have previously established a collaboration to investigate the epigenetics of SZ using a case-control approach with existing samples by collaborating with three large Consortia focusing on the genetics of SZ (MGI, COGS, PAARTNERS) that have already carried out extensive genetic and phenotypic studies on well-characterized patients, including quantitative neurocognitive phenotypes. Here we approach the epigenetics of SZ in the family members of the probands currently under study, as well as the relationship of epigenetic variation to quantitative neurocognitive phenotypes such as executive function, memory, language and emotion processing. Our Specific Aims are: (2) To quantitatively assess methylation of >4 million CpG sites genome-wide, across 1000 SZ families, examining an average of 3 family members per proband with a total of 3000 family members;(2) To use these data to estimate the heritability of genome-wide methylation in SZ families, to perform family-based epigenetic association with SZ and to perform family-based integration of GWAS data with DNAm;and (3) to examine neurocognitive phenotypes available across families to estimate the relationship between methylation and cognitive efficiency within and across families. The proposed research offers a novel, timely, powerful, and comprehensive strategy for determining the familial epigenetic contribution to SZ, combining expertise in epigenetic technology of human disease with a network of collaborating consortia yielding large well-characterized samples of patients with SZ and their family members. PUBLIC HEALTH RELEVANCE: Schizophrenia is a common, profoundly disabling disorder that carries a heavy burden for patients and families that is the subject of intensive genetic studies, but the study of epigenetic variation, such as DNA methylation, is an essential complement to conventional genetic disease studies, as epigenetic marks are affected by age and the environment. This project will provide a comprehensive genome-wide approach to the familial basis of schizophrenia, leveraging our ongoing study of an existing cohort of schizophrenic patients by examining family members for heritability of schizophrenia-related methylation changes, and by relating these changes to quantitative defects in cognition in patients and family members. The research offers a novel, timely, and powerful strategy for determining the familial epigenetic contribution to schizophrenia.
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0.958 |
2010 — 2013 |
Braff, David L. |
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. |
1/6-the Genetics of Endophenotypes and Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): The Consortium on the Genetics of Schizophrenia (COGS-2) is a 6-site collaborative linked R01 study that aims to understand the genetic architecture of functionally important quantitative neurophysiological and neurocognitive endophenotypes and the qualitative phenotype of schizophrenia in 2,000 patients and 1,000 community comparison subjects (CCS). During the initial support period, the COGS-1 project developed a robust research platform for subject recruitment, careful clinical characterization, acquisition, quality assurance, and analysis of these endophenotypes in probands (N=305), clinically unaffected family members (N=1,014) and CCS (N=505). In addition, COGS-1 developed novel statistical genetics methods that take full advantage of the unique findings that have emerged to date. The COGS-2 renewal will extend the use of the original 3 neurophysiological and 3 neurocognitive endophenotypes, as well as additional heritable endophenotypes derived from COGS-1 using the Computerized Neurocognitive Battery (CNB). Given the increased importance of the relationship of these endophenotypes to functional outcome, COGS-2 will also add a functional status assessment battery, consisting of observer-based, surrogate and real-world functional status. COGS-2 will complete the originally proposed linkage analysis in the COGS-1 sample, as well as conduct a candidate gene study from the COGS-1 database using the custom COGS 1536 SNP Chip. COGS-2 will focus on ascertaining, testing and obtaining DNA from new samples of 2,000 schizophrenia patients and 1,000 CCS recruited via Specific Aim 1. In Specific Aim 2, a genome wide association study (GWAS) using the current and most informative platform at the Center for Inherited Disease Research (CIDR) will be performed using the COGS-2 case-control data on the 9 COGS-2 quantitative endophenotypes and the qualitative diagnosis of schizophrenia. A complementary association study, using many strong-inference derived SNPs not included in the CIDR platform, will utilize the COGS SNP Chip array (94 candidate genes, 1536 SNPs) to assess SNP and copy-number variations (CNVs) associated with endophenotype deficits in schizophrenia as well as schizophrenia itself. In Specific Aim 3, SNPs and CNVs associated with these endophenotypes and schizophrenia will be compared with those in publicly available databases (e.g., GAIN, CATIE, BROAD). Furthermore, we will continue to develop the COGS platform and related innovative statistical genetics methods to identify and interrogate crucial genetic data in order to enhance the search for schizophrenia vulnerability genes, enhance the endophenotype strategy and ultimately identify molecular targets for the treatment and improved function of schizophrenia patients. PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating brain disorder that strikes young adults and carries with it a profound and devastating disease burden, often for the lifetime of the patient. The Consortium on the Genetics of Schizophrenia (COGS-2) project entitled, The Genetics of Endophenotypes and Schizophrenia, examines the genetic basis of impairments in core neurophysiological and neurocognitive processes in schizophrenia patients. Once we understand the genetic architecture of these abnormalities, new medications that aim to improve the functioning and quality of life of schizophrenia patients can be developed.
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0.958 |
2011 — 2015 |
Braff, David L. |
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. |
Gating and Inhibiting in Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): This cross-species translational research program will use laboratory-based inhibitory biomarkers (IBs) to understand the genetic and neurobiological basis for the "group of schizophrenias." The overarching goal of this project is to identify genetic variation associated with deficits in specific IBs in schizophrenia patients, and in parallel, to use animal model studies to clarify the neurobiological mechanisms linking these genes and IB deficits, i.e. the "gene-to-phene gap." In schizophrenia patients and normal comparison subjects, measures will assess 3 extensively studied primary IBs with known schizophrenia-linked deficits - prepulse inhibition of startle (PPI), startle habituation (HAB), and event related potentials (ERPs). IBs, their interrelationships, and associations with demographic, clinical, neurocognitive and functional outcomes will be examined. In mice and rats, PPI, HAB, and ERPs will be measured. In Aim 1, haplotype analyses will refine our preliminary IB-gene results. The genetic architecture of each IB in schizophrenia patients will be examined, focusing on 3 genes - NRG1;ERBB4;and COMT - together with other secondary genes of interest, based on preliminary association findings and/or the extant literature. Gene path analyses will more clearly define gene-gene interactions underlying biomarker-defined subgroups. Aim 2 will test 400 new schizophrenia patients and 400 new normal comparison subjects. These 800 new subjects will provide the power necessary to conduct the proposed behavioral and genetic analyses. Fine mapping will be performed to clarify the genetic substrates of biomarkers using the inclusive sample as well biomarker-defined subgroups based on the extreme deciles and quartiles of the distribution of IB measures. In Aim 3, pharmacological and molecular studies in rodents will explicate novel genetic mechanisms underlying IB deficits by: 1) assessing the impact of neuregulin-1 fragments on the IB deficits induced by dopamine agonists and NMDA antagonists in rats and mice;2) assessing IB deficits in interneuron-specific ErbB4 "knock out" mice;and 3) characterizing "knock in" mice having Val/Val or Met/Met variants of the human COMT gene, complemented by regionally specific viral delivery of the COMT gene. Aim 4 will characterize changes in brain regional gene expression in rat models with construct validity for IB deficits in schizophrenia patients: neonatal ventral hippocampal lesions (NVHLs) and isolation rearing. RT-PCR studies in inbred rats will focus on genes found in preliminary cross-species studies to be associated with IB deficits (e.g. NRG1, ERBB4, COMT, GRID2, REELIN, and GRIN2B). Functional (neurochemical) consequences of differences in regional gene expression will also be confirmed in NVHL and isolation-reared rats. In aggregate, these 4 Aims will leverage powerful translational strategies to identify genes associated with IB deficits in schizophrenia patients, and to explicate the neurobiological mechanisms that mediate these associations. PUBLIC HEALTH RELEVANCE: This application will use cross-species, translational studies to identify genes associated with deficits in specific brain-based inhibitory measures in patients with schizophrenia, and will identify the neurobiological mechanisms responsible for these deficits. The proposed studies extend the long-standing UCSD Schizophrenia Research Program work that has pioneered the use of laboratory-based biomarkers in order to better understand the clinical, cognitive, and everyday functional deficits of schizophrenia patients. By understanding the genetic and neural substrates of schizophrenia, new strong inference-based and "personalized" treatments can be identified for this devastating and costly disorder.
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0.958 |
2012 — 2014 |
Braff, David L. |
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. |
2/5-Gentics of Transcriptional Endophenotypes For Schizophrenia @ University of California San Diego
DESCRIPTION (provided by applicant): Schizophrenia is a common and debilitating condition with high personal costs to affected individuals and their families as well as high societal costs. Relatively little is known about the pathophysiology of schizophrenia. Although there is strong evidence for a genetic component to risk of schizophrenia, few specific genes involved in its etiology have been identified. In this set of coordinated R01s, we propose to take an alternative approach to localizing genes influencing risk of schizophrenia, combining established intermediate risk factors for schizophrenia with identification of novel transcriptional endophenotypes and combining standard GWAS gene localization approaches with innovative methods utilizing joint analysis of association and linkage and joint analysis of genomic and transcriptomic evidence. We will utilize existing samples and data from three ongoing studies: the Consortium on the Genetics of Schizophrenia (COGS); the Multiplex Multigenerational Investigation of Schizophrenia (MGI); and the Project among African Americans to Explore Risks for Schizophrenia (PAARTNERS). These three family studies were designed to investigate genetic influences on schizophrenia using neurocognitive phenotypes associated with schizophrenia risk. We hypothesize that alterations in gene regulation are responsible for some portion of the genetic liability to schizophrenia. Thus, we will use RNA expression levels both as potential endophenotypes for schizophrenia and as an alternative method of genome scanning. Identification of transcriptional correlates of schizophrenia will be facilitated by use of a novel Endophenotype Ranking Value (ERV) that combines the strength of the genetic signal on a potential endophenotype with the strength of its correlation with the disease of interest (i.e. schizophrenia) in a single measure. We will conduct a conventional genome-wide association study (GWAS) for schizophrenia, for newly identified transcriptional endophenotypes, and for classical neurocognitive risk factors. We will also take advantage of the large families in these samples to conduct joint linkage and association. Finally we will combine genomic and transcriptomic lines of evidence in a joint test to identify genes influencing schizophrenia and associated neurocognitive risk factors. All data generated in the course of the project will be shared through dbGaP and the NIMH Genetics Repository. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify genes influencing risk of schizophrenia utilizing information from intermediate traits, including levels of gene expression and measures of cognitive function, in families from three genetic consortia. Integration of information from the proposed association and gene expression studies, along with information from ongoing studies of DNA methylation and structural variants in these same families, will contribute to our understanding of the basic biological processes underlying schizophrenia, has the potential to aid in diagnosis and prevention, and may suggest new avenues of treatment.
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0.958 |