| 2002 — 2006 |
Mackinnon, Dean Frederick |
K23Activity Code Description:
To provide support for the career development of investigators who have made a commitment of focus their research endeavors on patient-oriented research. This mechanism provides support for a 3 year minimum up to 5 year period of supervised study and research for clinically trained professionals who have the potential to develop into productive, clinical investigators. |
Etiologic Connections of Affective and Anxiety Disorders @ Johns Hopkins University
DESCRIPTION (provided by applicant): Affective disorder are common, severe, recurrent, heterogeneous psycniatric diseases with an elusive pathophysiology. Their clinical and etiological complexity may obscure efforts to uncover mechanisms and tc discover therapeutic agents against those mechanisms. One common clinical feature that heightens complexity is comorbid anxiety. Combined anxiety and affective disorder syndromes exacerbate functional morbidity and suffering of patients, but may also present an opportunity to discover shared etiologic factors The candidate for this career development award is an academic psychiatrist at a teaching hospital with a strong historical commitment to medical research. The candidate has already established a reputation as a clinical specialist in affective disorders and has a research background in the genetics of affective disorder; by the end of the award period he plans to have established firmly a clinical and research direction aimed a comorbid anxiety and affective disorders, with fluency in psychophysiological methods. The award will facilitate this process by providing the time and resources to pursue further training in psychophysiology, neuroscience, and genetics. The starting points for the proposed research are 1) epidemiological findings that bipolar and panic disorders commonly occur together (comorbid risk), 2) symptom provocation studies ir panic disorder that reveal latent panic vulnerability in relatives of panic disorder patients (familial risk), and 3 family study results that show both familial and comorbid risk for panic disorder. The research program proposed here will address further questions about the relationship of panic and bipolar disorders by the use of carbon dioxide inhalation to provoke panic symptoms in study subjects ascertained for genetic linkage study of bipolar disorder. Risk of panic response to carbon dioxide in subjects without prior panic disorder will be analyzed as a function of familial and comorbid risk (as compared to the risk in positive and negative control subjects). If there is a specific genetic risk factor for both bipolar and panic disorder in a subset of families, then familial and comorbid risk will interact to produce higher risk of provoked panic than will either risk factor alone. Results of this work will then be applied to ongoing genetic studies of bipolar disorder, and will inform the candidate's further research into affective and anxiety disorder etiology.
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| 2006 — 2007 |
Mackinnon, Dean Frederick |
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. |
A Collaborative Genomic Study of Bipolar Disoder @ Johns Hopkins University
[unreadable] DESCRIPTION (provided by applicant): Since 1988 the NIMH Genetics Initiative has supported a national resource for the study of bipolar disorder (BP). By 1997 153 multiplex families were assessed, providing cell lines, DNA, and anonymized clinical data. This is now a publicly available resource and analytic results have been published. A second effort commenced in 1998 to ascertain 500 new BP sib pairs and this goal has been exceeded with 523 additional BPI sib pairs ascertained, interviewed, and a DNA sample collected. A genome wide scan has been completed at the Center for Inherited Disease Research (CIDR) on 237 sib pair families and the remaining 309 families will be genotyped by CIDR during 2003. This resource, the largest of its kind, has revealed evidence for areas of linkage on chromosomes 6q and 17q. It has also provided confirmation of a locus on chromosome 22q and support for areas on 1p, 10p, 16p, 13q, and 21q. Accumulating linkage data has implicated other chromosomal regions. We propose an extension of the national genetic resource to include a sample of 5000 unrelated BP probands and 2000 parents for case-control, and family-based association studies. Control samples will be obtained through the NIMH Genetics Initiative national resource. Probands and parents will be ascertained and assessed at eleven sites (the ten sites previously participating plus Howard University, which will provide African-American probands). This sample will be a national resource for fine scale linkage disequilibrium mapping within regions of linkage, as well as candidate gene association studies. Parental DNAs in a subsample will allow control for ethnic stratification. Bioinformatics techniques will be developed and supported for genomic analysis of candidate regions, to assist selection of SNPs and other polymorphic markers (including surrounding and within candidate genes), and primer design. The genotyping will be coordinated across 8 labs with an informed step-wise approach, beginning with standard microsatellite mapping of the current set of 699 pedigrees, followed by contract genotyping of SNPs in an industrial laboratory, and continuing with follow-up genotyping and sequencing of candidate genes and regions in laboratories at the individual sites. SNP typing of the larger case-control sample will occur in the final year of the collaborative study. Analysis of the existing sib pair families plus this large set of cases and controls should permit the confirmation of several vulnerability genes during this grant period. [unreadable] [unreadable]
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