This is a Shannon award providing partial support for the research projects that fall short of the assigned Institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. DESCRIPTION: Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in American men. There is currently an important need to develop better methods for diagnosis and prognosis of prostate cancer. A cellular hallmark of the transformed phenotype is abnormal nuclear shape, the presence of multiple nucleoli and altered patterns of chromatin organization. Nuclear structural alterations are so prevalent in cancer cells that they are commonly used as a pathological marker of transformation for many types of cancer. Nuclear shape is determined, in part, by the nuclear matrix, the dynamic skeleton of the nucleus. The nuclear matrix is the structural component of the nucleus that determines nuclear morphology, organizes the DNA in a three-dimensional fashion that is tissue specific, and has a central role in the regulation of a number of nuclear processes including the regulation of gene expression. The evidence presented in this proposal demonstrates that nuclear matrix protein composition is altered when comparing the normal dorsal prostate with the spontaneously arisen Dunning rate prostate adenocarcinomas. Nuclear matrix proteins were identified that either were: present only in the normal prostate and were missing in the Dunning tumors (normal pattern); or found only in the Dunning tumors and missing in the normal prostate (prostate cancer pattern), with pairs of proteins whose presence or absence correlated with the metastatic ability of the subline. Based on such observations, Dr. Getzenberg and his associates hypothesize that alterations in nuclear matrix proteins may be a fundamental cause of, or major contributor to, the pattern of altered gene expression identified in prostate cancer. Specifically, the investigators propose to: 1) isolate and sequence the nuclear matrix proteins identified as being normal or cancer associated and the proteins which were found to differ with metastatic ability, produce both monoclonal and polyclonal antibodies against these nuclear matrix proteins, and clone the cDNAs encoding these proteins; 2) to test the functional significance of these nuclear matrix proteins, by utilizing cDNA expression studies, antibodies, and antisense constructs; and 3) to compare the nuclear matrix proteins altered in the rat model system with differences in nuclear matrix proteins previously identified in human prostate cancer, and in normal or benign prostate tissues. These studies are expected to demonstrate that the nuclear matrix plays a central role in the pathogenesis of prostate cancer and may provide useful tools for disease diagnosis and/or prognosis and offer new strategies for treatment.
