Diabetic autonomic neuropathy alters autonomic reflexes and is associated with morbidity and a poor prognosis for diabetic patients. A component of this dysfunction is due to altered visceral afferent neurons. Injury to visceral afferent neurons of the vagus and glossopharyngeal nerves disrupts important cardiovascular, respiratory and gastrointestinal reflexes. The objectives for this project are to better characterize diabetes induced alterations in visceral afferent neurons, and to study the actions of the neurotrophin family of neurotrophic factors in visceral afferent nerve function/dysfunction in diabetes. The investigators will test the hypotheses that diabetes induces metabolic, neurochemical, neuropathologic, microvascular and functional alterations in visceral afferent neurons that can be alleviated with appropriate neurotrophic support. They will use streptozotocin treated diabetic rats (with/without insulin replacement) to characterize diabetes induced alterations in visceral afferent nerves and their ganglia at various times after initiation of experimental diabetes. To determine whether an impairment of neurotrophin actions may be involved in diabetes induced alterations in visceral afferent neurons, they will assess whether the delivery of neurotrophins to visceral afferent neurons is affected by altered retrograde external transport and/or by altered levels of neurotrophins in diabetes, and the effect of diabetes on the presence of neurotrophin receptors. Finally, the ability of specific neurotrophins to alleviate diabetes induced alterations and to affect visceral afferent neurons in diabetes will be determined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS038845-01
Application #
2759671
Study Section
Special Emphasis Panel (ZRG2-NMS (01))
Program Officer
Nichols, Paul L
Project Start
1998-09-30
Project End
2001-09-29
Budget Start
1998-09-30
Budget End
1999-09-29
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817
Gouty, Shawn; Regalia, Jen; Cai, Fang et al. (2003) Alpha-lipoic acid treatment prevents the diabetes-induced attenuation of the afferent limb of the baroreceptor reflex in rats. Auton Neurosci 108:32-44
Cai, Fang; Helke, Cinda J (2003) Abnormal PI3 kinase/Akt signal pathway in vagal afferent neurons and vagus nerve of streptozotocin-diabetic rats. Brain Res Mol Brain Res 110:234-44
Lee, Paek Gyu; Cai, Fang; Helke, Cinda J (2002) Streptozotocin-induced diabetes reduces retrograde axonal transport in the afferent and efferent vagus nerve. Brain Res 941:127-36
Regalia, Jen; Cai, Fang; Helke, Cinda (2002) Streptozotocin-induced diabetes and the neurochemistry of vagal afferent neurons. Brain Res 938:7-14
Gouty, S; Regalia, J; Helke, C J (2001) Attenuation of the afferent limb of the baroreceptor reflex in streptozotocin-induced diabetic rats. Auton Neurosci 89:86-95
Lee, P G; Hohman, T C; Cai, F et al. (2001) Streptozotocin-induced diabetes causes metabolic changes and alterations in neurotrophin content and retrograde transport in the cervical vagus nerve. Exp Neurol 170:149-61
Lee, P; Zhuo, H; Helke, C J (2001) Axotomy alters neurotrophin and neurotrophin receptor mRNAs in the vagus nerve and nodose ganglion of the rat. Brain Res Mol Brain Res 87:31-41
Helke, C J; Verdier-Pinard, D (2000) Neurotrophins alter the numbers of neurotransmitter-ir mature vagal/glossopharyngeal visceral afferent neurons in vitro. Brain Res 884:206-12
Ichikawa, H; Helke, C J (1999) The coexistence of TrkA with putative transmitter agents and calcium-binding proteins in the vagal and glossopharyngeal sensory neurons of the adult rat. Brain Res 846:268-73