Target for drug discovery, gene therapy and to create a diagnostic tool relevant to conditions involving inappropriate cell proliferation.
Reactive oxygen species (ROS) include superoxide and hydrogen peroxide. ROS are increasingly being recognized as playing a central role in diverse physiologic and pathologic processes. When produced in high amounts, for example by specific immune cells, ROS are chemically reactive, causing mutations and chemical damage to DNA, protein, biomembranes, etc. This property of ROS is utilized by immune cells to kill invading microbes, providing a first line of defense against infection. When produced at low levels by non-immune cells, ROS functions to regulate growth, apoptosis and in signal transduction. ROS are frequently considered to be an accidental byproduct of metabolism, particularly mitochondrial respiration. However ROS are also produced in a regulated manner in cells, for example, in response to growth factors and cytokines, and in this setting appear to function in regulation of cell division, angiogenesis and apoptosis. In this context, ROS appear to function pathologically as a mitogenic signal in diseases related to abnormal growth. These conditions include, but are not limited to, cancer, cardiovascular disease, and conditions relating to inappropriate angiogenesis. In addition, inappropriate generation of ROS plays a pathological role in tissue damage caused by inflammatory conditions such as arthritis, inflammatory bowel disease, shock lung, etc.
Drs. Lambeth and Cheng have discovered and molecularly cloned the cDNAs encoding a novel family of enzymes that generate ROS in a regulated manner,and appear to be a major source of ROS in a variety of cell types. This group of nucleotide sequences and their encoded proteins can be used to solve problems associated with the conditions listed above. The present invention describes cDNA clones and nucleotide sequences encoding novel regulatory subunits for these enzymes, vectors containing these sequences, cells transfected with these vectors that contain these nucleotide sequences or fragments thereof, and antibodies to amino acid sequences encoded by these cDNAs. The antibodies are useful for the detection, localization and measurement of the enzymes. The cDNAs are useful for transfection of cells to produce the proteins, and are needed for development of assay systems that are useful for the discovery of inhibitors of Nox enzymes. These inhibitors may be useful as drugs for the treatment of cancer, atherosclerosis and hypertension, prostatic hypertrophy and other disorders of abnormal cell proliferation. Drugs developed in this manner may also be useful for the treatment of chronic or acute inflammatory conditions such as inflammatory bowel disease, arthritis, shock lung, etc., and may be useful in remodeling and growth of cartilage following joint damage. Similarly, the cDNA sequences are expected to be useful to develop strategies for gene therapy approaches to treat the same conditions.