1998 — 2002 |
Zimmer, Warren E |
P60Activity Code Description: To support a multipurpose unit designed to bring together into a common focus divergent but related facilities within a given community. It may be based in a university or may involve other locally available resources, such as hospitals, computer facilities, regional centers, and primate colonies. It may include specialized centers, program projects and projects as integral components. Regardless of the facilities available to a program, it usually includes the following objectives: to foster biomedical research and development at both the fundamental and clinical levels; to initiate and expand community education, screening, and counseling programs; and to educate medical and allied health professionals concerning the problems of diagnosis and treatment of a specific disease. |
Germline Mutation of Mouse Beta Maj Gene--Transgenic Model of Sickle Cell Disease @ University of South Alabama
(Adapted from the Applicant's Abstract) Sickle cell disease arises from a genetic mutation in the adult beta-globin protein which results in the substitution of a valine for glutamic acid in position 6 of the molecule. It is a disease of chronic anemia that exhibits a complex pathophysiology. Although much is known about the disease, there is no cure or effective treatment currently available. A major impediment towards a detailed understanding of this disease and to the development of effective treatments is the lack of a suitable animal model. To provide systems allowing examination of chronic sickle cell disease events, a major focus of research effort has been the creation of transgenic mouse models. The introduction of human beta-s gene have, however, not created successful models due in part to expression rates of the transgene and the incompatibility of human and mouse globin proteins. Therefore, the investigators believe that a better model of sickle cell disease can be created by manipulation of the endogenous mouse betaMAJ gene. The investigators will test the hypothesis using a combined in vitro and in vivo approach. First, the investigators will express mouse globin in bacteria (Zimmer, 1996) then assay the expressed proteins, both normal and mutant, for oxygen carrying capacity and polymer formation. The investigators will utilize state of the art molecular modeling to guide the creation of mutant mouse beta globins that enhances polymer function. The investigators will then translate their in vitro knowledge to a mouse model by placing the appropriate mutations into the betaMAJ globin gene within mouse genome. This will use the technologies of targeted oblation (Zimmer, 1995) and replacement with the mutant betaMAJ gene sequences. The studies will create an animal model that more closely resembles the human disease. This will be key in understanding of the complex pathophysiology of sickle cell disease as well as a powerful tool to examine potential therapies.
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2003 — 2006 |
Zimmer, Warren E |
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. |
Prostate Epithelial Cell-Specific Gene Regulation @ University of South Alabama
[unreadable] DESCRIPTION (provided by applicant): We have demonstrated that the homeodomain Nkx 3.1 is a potent activator of the smooth muscle gamma actin [SMGA] gene. Although Nkx 3.1 is expressed in a variety of embryonic tissues, it is an androgen regulated gene product whose expression in adults is largely restricted to the male urogenital tract, primarily prostatic epithelia. Recent experiments from our lab has demonstrated that SMGA mRNA is expressed in normal and cancerous prostate epithelial cells. Moreover, SMGA expression [protein and mRNA] has been demonstrated in prostatic epithelia and exhibit a change in expression in carcinogenic cells. Thus, we believe that SMGA represents a novel product of differentiated epithelia. To test this hypothesis, we will determine SMGA temporal and spatial expression during prostate development [AIM I]. These studies will utilize in situ, immunochemistry and transgenic techniques to determine if SMGA is activated in parallel with Nkx 3.1 in early prostate epithelial cell development or with its increased androgen-responsive expression obtained with puberty. We will also directly compare mouse and human prostate development and determine whether or not there is a link of SMGA expression or cellular localization with the progression of cancer. Further, we will determine the mechanism(s) that Nkx 3.1 and SRF utilize to activate prostatic SMGA expression and determine if interaction of these regulators is capable of reversing the aberrant growth control of prostatic tumor cells [AIM II]. Finally, we will utilize novel Cre/LoxP technologies to ablate the expression of SMGA and its regulator, Nkx 3.1, in developing and mature prostate epithelia [AIM III]. These experiments will determine the consequences of specifically eliminating these genes upon prostate morphological and functional capacity. When completed, these studies will provide a new understanding of the molecular mechanisms that underlie Prostate development. In addition, our studies will potentially develop new models of prostate cancer, thus providing not only an avenue for greater comprehension of prostate carcinogenesis, but also strategic knowledge for further studies to design molecular based therapies for advanced prostate cancer.
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