MTbx protein and nucleic acid molecules and uses therefor

Details MTbx protein and nucleic acid molecules and uses therefor MTbx protein and nucleic acid molecules and uses therefor

2000-02-28

2001-09-18

Carlson, Karen Cochrane (Department: 1653)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C530S350000, C435S006120, C435S320100, C435S325000, C435S252300, C536S023100

Reexamination Certificate

active

06291193

ABSTRACT:

BACKGROUND OF THE INVENTION
The precise regulation of the events occurring during embryonic development as well as during tissue repair in adult organ systems is modulated in part by transcription factors.
Certain disease states, such as Dilated Cardiomyopathy (DCM), have been linked to inappropriate transcriptional regulation. DCM is a leading cause of cardiovascular morbidity and mortality and is characterized as a heterogeneous group of myocardial diseases characterized by cardiac dilation and impaired myocardial contractility (Richardson, P. et al (1996) Report of the 1995 World Health Organization/Intentional Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies.
Circulation
93:841-842). This syndrome consists of ventricular enlargement, abnormal systolic and diastolic left ventricular function, symptoms of congestive heart failure, and premature death due predominantly to heart failure and cardiac arrhythmias. Coronary artery disease, valvular heart disease, viral infection, toxins, autoimmunity, and primary genetic abnormalities can all cause dilated cardiomyopathy, but in many patients it is idiopathic (Leiden, J. M. (1997)
N Engl J Med
337:1080-1081). Studies have indicated that a common set of molecular and cellular pathways accounts for the progression of this disease.
To date, two classes of genes have been implicated in DCM. The first class comprises genes that encode structural proteins like dystrophin (Muntoni, F. et al (1993)
N Engl. J Med
329:921-925) and muscle LIM (Lin-11, Isl-1, and Mec-3) protein (Arber, S. et al (1997)
Cell
88:393-403; Arber, S. et al (1994)
Cell
79:221-231). These proteins organize the contractile apparatus of cardiac myocytes and ensure their structural integrity. A related disease, Marfan's syndrome, also effects the cellular-extracellular relationship in the heart. Marfan's syndrome is an autosomal dominant disorder of connective tissue that is characterized by ocular, skeletal, and cardiovascular manifestations. With a combination of diligent tracking of the cardiovascular status of Marfan's patients, prophylactic aortic-root replacement, and the use of beta-adrenergic-blocking agents morbidity and mortality from cardiovascular failure has decreased. The effective treatment of patients with Marfan's syndrome relies on early and accurate diagnosis. Heretofore, there has been a lack of sensitive and specific diagnostic tests for the disorder. A cause-and-effect relationship has been determined between mutations in the fibrillin gene (a glycoprotein component of the extracellular microfibril) and the Marfan's phenotype (Dietz, H. C. et al (1991)
Nature
352:337-339).
A second class of genes, those which encode transcription factors that control the expression of cardiac myocyte genes, have also been implicated in DCM. For example, the cyclic AMP response-element binding protein (CREB) is a basic leucine-zipper nuclear transcription factor that regulates the expression of genes in response to a wide variety of extracellular signals. A dominant-negative CREB mouse model revaled a four chambered DCM phenotype closely resembling many of the anatomical, physiological, and clinical features of human Idiopathic-Dilated Cardiomyopathy (IDC) wherein monocyte numbers decreased, interstitial fibrosis occurred and impaired systolic and diastolic left ventriccular function was in evidence (Fentzke R. C. et al (1998)
J Clin Invest
101 (11):2415-2426). Expression of certain “fetal” genes, which are normally repressed after embryonic development, is a common feature in cardiac hypertrophy. A transcription factor that has been implicated in cardiac function and specifically in the developmental progression of cardiac organogenesis is nuclear factor of activated T cells (NF-ATc). Studies with NF-ATc nonsense-mutation mouse models reveal that NF-ATc is required for the proper development of the pulmonary and aortic vales and septum in the heart. (de la Pompa, J. L. et al (1998)
Nature
392:182-186; Ranger, A. M. (1998)
Nature
392:186-190) NF-ATc, having translocated to the nucleus via a calcineurin mediated pathway, may be able to form a complex with a developmentally expressed transcription factor, GATA-4, to activate so-called fetal genes (Molkentin, J. D. et al (1998)
Cell
93 (2):215-28). Geneticists have identified five additional loci associated with adult-onset autosomal dominant dilated cardiomyopathy. Soon it will be possible to correlate clinical outcome with genetic susceptibility profiles, as has been reported for patients with hypertrophic cardiomyopathy.
The immune system is a highly regulated and plastic system with a variety of stimulatory and responsive elements. One modality for the regulation of stimulus response and the subsequent exquisitely controlled response is via transcription factors which act on a variety of genes in the immune system singularly and in concert with one another. One example of such a transcription factor is nuclear factor-(kappa)B (NF-&kgr;B). This factor regulates the expression of many of the genes involved in proinflammatory pathways such as cytokines, chemokines, enzymes involved in mediation inflammation, immune receptors and adhesion molecules involved in the initial recruitment of leukocytes to sites of inflammation (Stein, B. and Baldwin, A. S. (1993)
Mol Cell Biol
13:7191-7198; Kopp, E. B. and Ghosh, S. (1995)
Adv Immunol
58:1-27). It plays a role in asthma, ulcerative colitis and rheumatoid arthritis by regulating the expression of the inducible gene for nitric oxide synthase (Xie, Q. W. et al (1994)
J Biol Chem
269:4705-4708) and it modulates the onset of inflammatory disease via the regulation of cyclooxygenase-2 increasing the production of prostaglandins and thromgboxanes (Yarnamoto, K. et al (1995)
J Biol Chem
270:31315-50; Crofford, L. J. et al (1994 )
J Clin Invest
93:1095-101). Changes in the expression or activation of specific oncogenes encoding transcription factors cause many leukemias characterized by particular chromosomal translocations (Rabbitts, T. H. (1994)
Nature
372:143-9.). T-cell acute leukemias may have a variety of genes fused to their T-cell-receptor gene loci, but the fusion partners have a common function: they are almost all genes for transcription factors (Fisch, P. et al (1992)
Oncogene
7:2389-97; Korsmeyer, S. J. (1992)
Anny Rev Immunol
10:785-807; Cleary, M. L. (1991)
Cell
66:619-22; Cline, M. J. (1996)
N Engl J Med
330:328-336), for example, in acute childhood leukemia the expression of the homeobox-containing gene HOX-11 is activated by translocation to the T-cell receptor locus (Hatano, M. et al (1991)
Science
253:79-82). The molecular characterization of the defects associated with diseases such as are stated herein point the way towards therapeutic approaches. Immunosuppressive agents such as cyclosporin and tacrolimus (FK 506) exert their effects by inhibiting specific transcription factors that are required for T-cell activation (Liu, J. et al (1991)
Cell
66:807-15). Thus, it is clear that a greater understanding of role which transcription factors play on the immune system would lead to the determination of highly specific drug targets which would work to treat immune system disorders, such as chronic inflammatory disease.
Other embryonic developmental transcription factors play integral roles in organogenesis and tissue repair. A subset of these factors, called T-Box transcription factors, share several common features: DNA-binding and transcriptional regulatory activity; retention of conserved expression patterns between orthologs and within subfamilies; modulation of regulatory pathways; mediation of mesodermal induction as well as other inductive interactions; and some modulate embryogenesis, organogenesis, organ regeneration, and tissue repair.
The mouse Brachyury (T) gene was the first T-Box gene to be discovered (Dobrovolskaia-Zavadskaia, N. (1927) C. R.
Seanc Soc Biol
97:114-116.) and it is by far the most studied. Recently it was identif

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