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Seal, Rebecca, PhD

University of Pittsburgh, Pittsburgh, Pennsylvania

Project Title:

The Role Of Vglut3 In Diabetic Neuropathic Pain

Grant Number:

7-12-IN-40

Type of Grant:

Innovation

General Research Subject:

Both Type 1 and Type 2 Diabetes

Project Start Date:

Jul 1, 2012

Project End Date:

Jun 30, 2014

Focus:

Complications, Complications\Neuropathy

Research Description



Patients suffering from diabetes often incur nerve damage do to aberrant blood-glucose levels. For a significant number of diabetes patients, this damage manifests itself as chronic pain hypersensitivity in the distal limbs, which is often refractive to treatment. In order to develop new treatments for this pain, it is important to understand the molecules and neural circuits that mediate it. In previous studies, we found that mice with a genetic deletion of the vesicular glutamate transporter (Vglut) 3 do not experience increased mechanical pain sensitivity in inflammatory, post-operative, or neuropathic models of chronic pain. Using these mice, we can now test whether Vglut3 has a similar role in the pain associated with diabetic neuropathy. Due to the highly specific nature of the pain defect in Vglut3 knockout mice, Vglut3 could be an extremely useful tool to further understand the molecular and anatomic mechanisms mediating painful diabetic neuropathy. In addition, there is a population of neurons in the spinal cord that are important for the mechanical pain hypersensitivity that occurs with nerve injury and in diabetes. We would like to understand the anatomical and functional relationships between these neurons and those that express Vglut3. Together these studies will provide a better understanding of the neural circuitry underlying painful diabetic neuropathy as well as its relationship to other forms of chronic pain. Such knowledge will provide new treatment strategies for this often debilitating condition.

Research Profile



What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Patients suffering from diabetes often incur nerve damage do to aberrant blood-glucose levels. For a significant number of diabetes patients, this damage manifests as pain in the distal limbs and is often refractive to treatment. In order to develop new treatments for this pain, it is important to identify the molecules and neural circuits that mediate it. In previous studies, our group found that mice with a genetic deletion of the vesicular glutamate transporter (VGLUT) 3 do not experience the mechanical pain hypersensitivity that normally occurs in inflammatory, post-operative, and neuropathic models of chronic pain. Using these mice, we will now test whether VGLUT3 has a similar role in the pain associated with diabetic neuropathy. Due to the highly specific nature of the pain defect in VGLUT3 knockout mice, studies of the transporter can potentially provide insight into the molecular and anatomical mechanisms underlying painful diabetic neuropathy and aid in the development of new therapeutic strategies for the treatment of this debilitating condition.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Painful diabetic neuropathy is a common complication of diabetes, but the underlying biological mechanisms responsible for this type of pain are not well understood nor are there good treatment options. Our work is focused on understanding these pathological mechanisms on a molecular, cellular and anatomical level and then using this information to identify new therapeutic targets to treat the pain.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Our laboratory is currently working to understand the molecular and anatomical basis of chronic mechanical pain that results from nerve and tissue damage. The vesicular neurotransmitter transporter we study, VGLUT3 is required for this type of pain and we hypothesize that it will also be required for a similar type of pain that develops in diabetics. The incidence of type 2 diabetes is escalating rapidly, and thus, so are the complications of this condition including chronic neuropathic pain. Since treatment options are limited for this type of pain, we believe that we have a tremendous opportunity to provide needed insight into the biology underlying diabetic neuropathic pain, which can then be used to develop new treatment options. This ADA award will allow us to carryout these critical initial studies.

In what direction do you see the future of diabetes research going?
Diabetic neuropathy results from injury to primary sensory neurons that innervate the extremities. Research that aims to prevent damage to these neurons could eventually reduce the development of neuropathic pain if diabetes is detected early. Unfortunately, in many cases, damage to the nerves has already occurred before diabetes is diagnosed. Detection of diabetes before irreversible nerve damage develops is obviously an important area of research. Nevertheless, since pain treatments are still needed, understanding the biological mechanisms that initiate and maintain this type of chronic mechanical pain will also be an active area of research. Investigators will continue to identify molecules, cells and circuits in the peripheral and central nervous systems that mediate this type of pain and use this information to develop new treatment strategies.