Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving transferase
Reexamination Certificate
2001-12-21
2004-11-02
Gitomer, Ralph (Department: 1651)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving transferase
C435S029000
Reexamination Certificate
active
06811993
ABSTRACT:
BACKGROUND
Recent studies have identified that hyperglycemia induces de novo diacylglycerol (DAG) synthesis and activates Protein Kinase C (PKC), which leads to many kinds of vascular abnormalities involving abnormalities of the retina, glomeruli and cardiovascular tissues. In clinical assessment, measurement of PKC activity in vascular tissues is desired, but it is not easy to obtain vascular samples from diabetic patients repeatedly.
SUMMARY OF THE INVENTION
The inventor has discovered that PKC activity, e.g., PKC&bgr; activity, in mononuclear cells, e.g., monocytes, correlates with PKC activity in other tissues, e.g., in vascular or cardiovascular tissue (e.g., in retinal, kidney or aorta vascular tissues or heart). Accordingly, the invention features a method of evaluating the level of PKC activity in a tissue other than monocytes of a subject, e.g., in vascular or cardiovascular tissue, e.g., in retinal, kidney or aorta vascular tissues or heart. The method includes evaluating the level of the PKC activity, e.g., PKC &bgr; activity, in mononuclear cells, e.g., monocytes, of the subject. The level of PKC activity in mononuclear cells is correlated with the level of PKC activity in other tissues, e.g., vascular tissue, e.g., in retinal, kidney or aorta vascular tissue or in heart. The subject can be a human, or any non-human animal, e.g., a non-human mammal, e.g., rodent, e.g., a mouse or a rat.
In a preferred embodiment, PKC&bgr; activity is evaluated.
In a preferred embodiment, the subject is a human.
In a preferred embodiment, the subject is an experimental animal.
The invention also features methods of evaluating a subject, e.g., staging of, evaluating the treatment of, or determining if a subject is at risk for (e.g., has a genetic disposition to), has a symptom of, or is afflicted with, a PKC related disorder, e.g., a disorder described herein, e.g., diabetes, diabetes mellitus, Type I diabetes, Type II diabetes, diabetic retinopathy, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, diabetic nephropathy, microalbumiuria, proteinuria, renal failure, cardiovascular disorder, hypertension, atherosclerosis, coronary artery spasm, congestive heart failure, coronary artery disease, valvular disease, arrhythmias, cardiomyopathy, aging, or an aging-related disorder. The method includes evaluating the level of PKC activity, e.g., PKC &bgr; activity, in mononuclear cells, e.g., monocytes, of the subject. Optionally, the method also includes comparing the level of the PKC activity in monocytes of the subject with a standard, e.g., the level of PKC activity in a control sample, e.g., a non-diabetic subject, a preset value, or a basal activity value.
In some embodiments, the level of the PKC activity in monocytes of a subject correlates with risk of developing a PKC-related disorder, e.g., diabetic retinopathy or another PKC related disorder described herein. For example, the level of PKC activity in monocytes of a subject correlates with a genetic predisposition to a PKC-related disorder, e.g., retinopathy.
In a preferred embodiment, PKC&bgr; activity is evaluated.
In a preferred embodiment, the subject is a human.
In a preferred embodiment, the subject is an experimental animal.
In another aspect, the invention features a method of evaluating a subject for the extent, stage, or severity, of a PKC related disorder, e.g., a disorder described herein, e.g., diabetes, diabetes mellitus, Type I diabetes, Type II diabetes, diabetic retinopathy, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, diabetic nephropathy, microalbumiuria, proteinuria, renal failure, cardiovascular disorder, hypertension, atherosclerosis, coronary artery spasm, congestive heart failure, coronary artery disease, valvular disease, arrhythmias, cardiomyopathy, aging, or an aging-related disorder. The method includes evaluating the level of PKC activity in monocytes of the subject and, optionally, comparing the level of the PKC activity in monocytes of the subject with a standard, e.g., a preset value, the level of PKC activity in a control sample or subject, or a basal activity value. The level of PKC activity in the monocytes is correlated, preferably positively, with the extent, stage, or severity, of the PKC related disorder.
In a preferred embodiment, PKC&bgr; activity is evaluated.
In a preferred embodiment, the subject is a human.
In a preferred embodiment, the subject is an experimental animal.
In another aspect, the invention features methods of evaluating the effect of a treatment for a PKC related disorder, e.g., diabetes, diabetes mellitus, Type I diabetes, Type II diabetes, diabetic retinopathy, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, diabetic nephropathy, microalbumiuria, proteinuria, renal failure, cardiovascular disorder, hypertension, atherosclerosis, coronary artery spasm, congestive heart failure, coronary artery disease, valvular disease, arrhythmias, cardiomyopathy, aging, or an aging-related disorder, which includes administering a treatment to a subject and measuring PKC activity, e.g., PKC &bgr; activity, in the subject's mononuclear cells, e.g., monocytes. The treatment can be, e.g., administration of a compound, e.g., a protein (e.g., an antibody or a hormone, e.g., insulin), a small molecule, a vaccine, a nucleic acid). The subject can be a human, or a non-human animal, e.g., a rat or a mouse, or an animal model for a disorder described herein, e.g., a NOD mouse and its related strains, BB Rat, Leptin or Leptin Receptor mutant rodents, Zucker Diabetic Fatty (ZDF) Rat, Obese Spontaneously Hypertensive Rat (SHROB, Koletsky Rat), Wistar Fatty Rat, New Zealand Obese Mouse, NSY Mouse, Goto-Kakizaki Rat, OLETF Rat, JCR:LA-cp Rat, Neonatally Streptozotocin-Induced (n-STZ) Diabetic Rats, Sprague-Dawley rat, Rhesus Monkey,
Psammomys obesus
(fat sand rat), C57B1/6J Mouse. The level of PKC activity in the monocytes is correlated with the effect of the treatment. The method can be used, e.g., to evaluate the effect of an experimental treatment, e.g., an experimental compound, or a known treatment, e.g., insulin.
In a preferred embodiment, PKC&bgr; activity is evaluated.
In a preferred embodiment, the subject is a human.
In a preferred embodiment, the subject is an experimental animal.
In yet another aspect, the invention features a method of identifying a compound for treating a PKC related disorder, e.g., diabetes, diabetes mellitus, Type I diabetes, Type II diabetes, diabetic retinopathy, proliferative diabetic retinopathy, non-proliferative diabetic retinopathy, diabetic nephropathy, microalbumiuria, proteinuria, renal failure, cardiovascular disorder, hypertension, atherosclerosis, coronary artery spasm, congestive heart failure, coronary artery disease, valvular disease, arrhythmias, cardiomyopathy, aging, or an aging-related disorder. The method includes administering a test compound to a subject, e.g., an animal, e.g., a mouse or a rat, or an animal model for a disorder described herein, and measuring PKC activity, e.g., PKC &bgr; activity, in mononuclear cells, e.g., monocytes, of the subject. The level of PKC activity in the monocytes is correlated with the effect of the treatment. The method may also optionally include identifying a subject in need of a treatment for the PKC related disorder, and comparing the PKC activity, e.g., PKC &bgr; activity, in monocytes, after administration of a test compound, to a standard. A compound for the treatment of the disorder is identified when the PKC activity after the administration of the compound is altered, e.g., increased or decreased, as compared to a standard, e.g., a preset value, the level of PKC activity in a control sample, a basal activity value, or the PKC activity before, or in the absence of, the administration of the compound.
In a preferred embodiment, PKC&bgr; activity is evaluated.
In a preferred embodiment, the subject is a human.
In a preferred embodiment, the subject is an experimental animal.
In a preferred embodiment, the method fu
Fish & Richardson P.C.
Gitomer Ralph
Joslin Diabetes Center, Inc.
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