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JDRF Funded Research

JDRF-Funded Research:  Lay Abstract

Name:   Stephen Dewhurst ,Ph.D.
University of Rochester, USA
Lab Website:  

Project duration:   01-SEP-2010   to   31-AUG-2012
Strategic Research Agreement

Project grant award:   $280,820.81*

* Total Grant award amount may vary depending on budget adjustments and it is contingent upon research progress and availability of JDRF research funds.
File No:   17-2010-795

(Abstract Dt: 24-MAY-2010)

Therapeutic Area:   Complications Therapies

Grant Status: Inactive
Project Title
DLK/MLK Inhibitors for the Treatment of Diabetic Neuropathy
Objective
In collaboration with Califia Bio, the University of Rochester Medical Center (URMC) has developed a novel series of chemical inhibitors of DLK and closely related members of the mixed lineage kinase (MLK) family. These novel inhibitors are highly selective, extremely potent and well suited for oral delivery. The overall goal of this project is to use these inhibitors to perform proof of concept studies that will test the hypothesis that DLK inhibition or combined pharmacologic DLK/MLK inhibition may be useful for the treatment or prevention of diabetic neuropathy.
Background/Rationale
According to the National Diabetes Information Clearinghouse (NDIC), some 60-70% of persons with diabetes suffer from neuropathy. Diabetic neuropathy (DN) leads to incapacitating pain, sensory loss, foot ulceration, gangrene, poor wound healing, and lower limb amputation. No specific therapy for DN is presently available, and pain management strategies fail to treat the underlying causes of DN. Diabetic neuropathy is associated with nerve degeneration, suggesting that nerve regeneration may have the potential to reverse and treat this disease. Recently, it has been recognized that a cellular kinase known as dual leucine zipper kinase (DLK) promotes nerve degeneration in mammals after nerve injury. This suggests that a chemical inhibitor of DLK may protect peripheral nerves from damage induced by exposure to high levels of glucose, as occurs in persons with diabetes.
Description of Project
BACKGROUND/RATIONALE: According to the National Diabetes Information Clearinghouse (NDIC), some 60-70% of persons with diabetes suffer from neuropathy. Diabetic neuropathy (DN) leads to incapacitating pain, sensory loss, foot ulceration, gangrene, poor wound healing, and lower limb amputation. No specific therapy for DN is presently available, and pain management strategies fail to treat the underlying causes of DN. Diabetic neuropathy is associated with nerve degeneration, suggesting that nerve regeneration may have the potential to reverse and treat this disease. Recently, it has been recognized that a cellular kinase known as dual leucine zipper kinase (DLK) promotes nerve degeneration in mammals after nerve injury. This suggests that a chemical inhibitor of DLK may protect peripheral nerves from damage induced by exposure to high levels of glucose, as occurs in persons with diabetes. OBJECTIVE: In collaboration with Califia Bio, the University of Rochester Medical Center (URMC) has developed a novel series of chemical inhibitors of DLK and closely related members of the mixed lineage kinase (MLK) family. These novel inhibitors are highly selective, extremely potent and well suited for oral delivery. The overall goal of this project is to use these inhibitors to perform proof of concept studies that will test the hypothesis that DLK inhibition or combined pharmacologic DLK/MLK inhibition may be useful for the treatment or prevention of diabetic neuropathy. ANTICIPATED OUTCOME: If the proposal is successful, it will result in the identification of a new molecular target for the treatment of diabetic neuropathy. It will also result in the generation of new drugs with the demonstrated ability to treat diabetic neuropathy in a relevant small animal model system. Thus, at the conclusion of the proposed funding period, we expect to have identified new drugs that could be rapidly moved forward for clinical testing in persons with diabetic neuropathy. RELEVANCE TO TYPE 1 DIABETES: According to the National Diabetes Information Clearinghouse (NDIC), some 60-70% of persons with diabetes suffer from neuropathy. The rate is higher in older persons and persons who have had diabetes for an extended period, as well as in persons who are overweight and/or who have difficulty controlling their blood sugar. Diabetic neuropathy affects persons with both Type 1 and Type 2 diabetes.
Anticipated Outcome
If the proposal is successful, it will result in the identification of a new molecular target for the treatment of diabetic neuropathy. It will also result in the generation of new drugs with the demonstrated ability to treat diabetic neuropathy in a relevant small animal model system. Thus, at the conclusion of the proposed funding period, we expect to have identified new drugs that could be rapidly moved forward for clinical testing in persons with diabetic neuropathy.
Relevance to Type I Diabetes
According to the National Diabetes Information Clearinghouse (NDIC), some 60-70% of persons with diabetes suffer from neuropathy. The rate is higher in older persons and persons who have had diabetes for an extended period, as well as in persons who are overweight and/or who have difficulty controlling their blood sugar. Diabetic neuropathy affects persons with both Type 1 and Type 2 diabetes.