Caspases in Cell Death & Disease
Apoptosis is a complex mechanism of programmed cell death that is controlled by multiple biochemical events leading to morphological cell changes and eventual cell death. The apoptosis process begins when apoptotic signals cause regulatory proteins to initiate an apoptosis pathway. The primary pathways targeted include mitochondrial functionality, transduced signals via adaptor proteins to the apoptotic mechanism, and drug induced increases in calcium within the cell. Apoptosis culminates in coordinated cell death that requires energy and, unlike cell death occurring by necrosis, does not involve an inflammatory response.
Apoptosis is a critical event in numerous processes within the body. For example, embryonic development relies on apoptosis, and tissues that turn over rapidly require tight regulation to avoid serious pathological consequences. Cancer can be characterized by insufficient apoptosis and uncontrolled cell proliferation brought on in part by failure to regulate apoptosis. In treating such conditions, apoptosis can be induced by various means. On the other hand, neurodegenerative disorders such as Alzheimer’s disease, excess apoptosis can damage organs. Apoptosis can also be indicative of tissue damage, such as damaged heart tissue following ischemia or reperfusion insults.
Cellular pathways leading to both apoptosis and inflammation involve the activation of members of a protease family of caspases. At least 14 members of the caspase family have been identified in vertebrates, and at least 8 are known to be involved in apoptotic cell death. Caspases are a group of highly specific cysteine proteases that cleave aspartic acid peptide bonds with proteins. Caspases collaborate in the proteolytic cascade by activating themselves and each other. Apoptosis-related caspases can be divided into two categories: “initiator” caspases (e.g., caspase-2, caspase-8, caspase-9 and caspase-10), and downstream “effector” caspases (e.g., caspase-3, caspase-6, caspase-7 and caspase-14). Initiator caspases mediate their oligomerization and autoactivation in response to specific upstream signals, and can activate effector caspases by cleaving their inactive pro-forms. Activated effector caspases trigger the apoptotic process by cleaving protein substrates within a cell. Caspase inhibitors can thus regulate the initiation of the apoptotic caspase chain reaction.
Other caspases (e.g., caspase-1, caspase-4, caspase-5, caspase-11 and caspase-13) are involved in inflammatory pathways. One such inflammation-related caspase (i.e., caspase-1) was first identified as an IL-1 converting enzyme (ICE-1) required for activatiion of the IL-1 beta and IL-18 cytokines in inflammatory responses. The detection of active caspases involved in inflammatory pathways indicates an acute or chronic inflammatory response - e.g., inflammation associated with inflammatory diseases such as rheumatoid arthritis or atherosclerosis.
The utility of monitoring caspases in disease provides value during the entire drug discovery process as well as potential value for clinical diagnostics. Vergent Bioscience has currently built its scientific platform largely on imaging probes to detect caspase activity within disease conditions. Imaging probes are currently available for the research market.
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