Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-10-31
2003-12-30
Kemmerer, Elizabeth (Department: 1645)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S005000, C435S006120, C435S007920, C424S130100, C530S300000, C530S350000
Reexamination Certificate
active
06670138
ABSTRACT:
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TECHNICAL FIELD
The present invention relates to methods for diagnosing or assessing an individual's susceptibility to a neurological disorder or a neuronal injury. The invention also relates to therapeutic methods for treating an individual suffering from a neurological disorder or a neuronal injury and methods for identifying agents that can be administered to treat such an individual.
BACKGROUND OF THE INVENTION
Uncoupling proteins (UCPs; thermogenins) are proton-translocating proteins located in the inner mitochondrial membrane that play a role in metabolic processes, particularly non-shivering thermogenesis. The first UCP (UCP-1) was found to be localized in the brown adipose tissue, specialized fat cells that function in heat generation and energy balance. Hibernating and cold-adapted animals have significant stores of such tissue. The evidence indicates that UCPs function to maintain the core body temperature of hibernating mammals and other cold-adapted animals by raising the resting metabolic rate of the animals (see, e.g., Nicolls, D. G. and Locke, R. M. (1984) Physiol. Rev. 64:2-40; and Rothwell, N.J., and Stock, M. J. (1979) Nature 281:31-35).
As the name indicates, UCPs serve an uncoupling function, specifically by uncoupling proton flux through the mitochondrial membranes and ATP synthesis. The mitochondrial oxidation of metabolites (e.g., pyravate and fatty acids) is accompanied by proton transport out of the mitochondrial matrix, thereby generating a transmembrane proton gradient. The protons re-enter the mitochondria through the protein ATP synthase and drive the synthesis of ATP. The UCPs, however, provide a route for the re-entry of the protons that is uncoupled to ATP synthesis. Consequently, instead of the proton gradient resulting in the generation of ATP, UCPs act to covert the proton gradient into heat energy and increase the rate of respiration. Exposure to the cold triggers the neural and hormonal stimulation of brown adipose tissue, which in turn increases UCP-mediated proton transport and heat production (see, e.g., Susulic, V. S., and Lowell, B. B. (1996) Curr. Opin. in Endocrinol. and Meta. 3:44-50). Studies conducted with various transgenic models have demonstrated that a reduction in UCP activity correlates with the development of obesity and diabetes (see, e.g., Lowell, B. B., et al. (1993) Nature 366:740; and Kopecky, J. et al. (1995) J. Clin. Invest. 96:2914-23).
While humans have a UCP-1 gene that is active in brown fat, these fat deposits disappear shortly after birth (see, e.g., Bouillaud, et al. (1985) Proc. Natl. Acad. Sci. 82:445-448). Nonetheless, measurements showing that 25% to 30% of the oxygen that humans and other animals utilize to metabolize their food is used to compensate for mitochondrial proton leaks suggested the presence of other UCPs in humans. In fact, several human UCPs have now been identified.
One such UCP is referred to in the literature as UCP-2 or UCPH. The gene encoding this protein maps to human chromosome 11 and has been linked to hyperinsulinemia and obesity. UCP-2 is reported to be expressed in various adult tissue, including brain, muscle and fat cells (see, e.g., Fleury, et al. (1997) Nat. Genet. 15:269-272; Tartaglia, et al. PCT Publication No. WO 96/05861; Gimeno, et al. (1997) Diabetes 46:900-906; and Boss, et al. (1997) FEBS Letters 408:39-42). Allelic variants of UCP-2 appear to have been identified. While some UCP-2 proteins have an alanine at position 55 (see, Fleury, supra, and PCT Publication No. WO 00/06087), other UCP-2 proteins have a valine (see, PCT Publication WO 96/05861). At position 219, some UCP-2 proteins have a threonine (see, PCT Publication WO 96/05861 and PCT Publication WO 00/06087), whereas other UCP-2 proteins have an isoleucine (see, Fleury, supra). Methods for screening for allelic variants are discussed in PCT Publication WO 99/48905.
A third human UCP (UCP-3) has also been recently reported. This UCP is preferentially expressed in human skeletal muscle. The gene encoding this particular UCP maps to human chromosome 11, adjacent to the gene for UCP-2. Studies indicate that UCP-3 expression can be regulated by known thermogenic stimuli such as leptin, &bgr;-adrenergic agonists and thyroid hormone (see, e.g., PCT publication WO 98/45313; Boss, et al., (1997) FEBS Letters 408:39-42; Vidal-Puig, et al. (1997) J. Biol. Chem. 272:24129-24132; Solanes et al. (1997) J. Biol. Chem. 272:25433-25436; and Gong, et al. (1997) J. Biol. Chem. 272:24129-24312).
A fourth human UCP (UCP-4) has been identified. This UCP is expressed in a number of different tissues including, brain, heart, pancreas and muscle tissue (see, e.g., PCT Publication WO 00/04037). Another human UCP (UCP5/BMCP1) is most abundantly expressed in the brain, and at lower levels in most peripheral organs (Sanchis, et al. (1998) J. Biol. Chem. 273: 36411, and PCT Publication WO 00/032624).
Because of the role UCPs play in uncoupling the oxidation of metabolites and the storage of the resulting energy in the form of ATP, UCPs have been viewed primarily as targets for controlling a number of weight disorders (e.g., obesity and underweight disorders), as well as related diseases (e.g., diabetes). However, there is a paucity of information regarding other physiological functions of UCP and how UCP can be utilized in other types of applications other than weight-related applications.
SUMMARY OF THE INVENTION
Provided herein are various methods for diagnosing and treating various neurological disorders and neuronal injuries, particularly stroke and ischemic stroke. Methods for screening agents to identify agents useful in treating neurological disorders and injuries are also provided.
More specifically, certain methods involve diagnosing the occurrence of a stroke or assessing a patient's susceptibility to a stroke by detecting in a patient sample an elevated level of UCP-2 expression. In some methods, detection is accomplished by detecting elevated levels of UCP-2 transcript. Other methods involve detecting an elevated level of UCP-2 polypeptide. Elevated levels of UCP-2 polypeptide can be detected using various immunological techniques such as ELISA assays.
Some of the diagnostic methods provided herein involve assessing a patient's risk of having a stroke. Such methods involve comparing the level of UCP-2 expression in a test sample from the patient with a baseline value, wherein an elevated level of UCP-2 expression in the patient sample relative to the baseline indicates that the patient is at risk for stroke. A variety of baseline levels can be utilized in these methods. In some instances the baseline is the level of UCP-2 expression in a patient sample obtained previously. In other methods, the baseline value is an average value, a mean value or another statistical value for a population of control individuals.
Certain treatment methods provided herein involve treating a subject having or being susceptible to a neurological disorder or a neuronal injury by administering to the subject an effective amount of an agent that increases the activity of UCP-2. The neurological disorders or neuronal injuries that are amenable to the methods include stroke, Parkinson's disease, Huntington's disease, inherited ataxias, motor neuron diseases, Alzheimer's disease, epilepsy and traumatic brain injury. If the subject is susceptible to the neurological disorder or the neuronal injury, the subject is administered a prophylactic amount of the agent prior to occurring of the disorder or the injury. If, however, the subject has already suffered the neurological disorder or the neuronal injury, then the subject is administered a therapeutic
Chin Daniel
Gonzalez-Zulueta Mirella
McFarland K.C.
Melcher Thorsten
Shamloo Mehrdad
AGY Therapeutics, Inc.
Kemmerer Elizabeth
Nichols Christopher James
Sherwood Pamela J.
Taylor Rebecca D.
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