Marangoni_Maria.pdf (3.51 MB)
Mechanism of Fast Axonal Transport Deficits in Diabetic Neuropathies
thesisposted on 2012-09-07, 00:00 authored by Maria N. Marangoni
Diabetic neuropathy (DN) is one of the most common long-term complications of diabetes mellitus (DM) with no available therapies due to the lack of understanding of pathogenic mechanisms for the disease. Impaired fast axonal transport (FAT) represents a candidate mechanism, but the molecular basis for transport changes in DN has never been explored. This work is the first report to describe a molecular mechanism for FAT deficits in DN. The streptozotocin (STZ) model for induction of type 1 DM was optimized in the Fischer 344 rat strain. Behavioral, physiological and biochemical measurements were used to characterize development of DN. Putative mechanisms for FAT deficits were evaluated by measuring the activation state of kinases pertinent to FAT regulation and kinesin binding to microtubules (MT) in DM nerves. This model developed sustained hyperglycemia typical of DM state. Moreover, this model consistently developed insensate neuropathy co-presenting with cardiovascular autonomic neuropathy in contrast to other DN animal models. Furthermore, this is the first report to elucidate a pattern of kinase activation relevant to FAT regulation consistent with deficient insulin signaling in both sciatic and vagus nerves. Further, STZ diabetic rats exhibited decreased kinesin binding to microtubules consistent with FAT deficits in DN.
AdvisorPiano, Mariann R.
Committee MemberBrady, Scott T. LaDu, Mary J. Unterman, Terry G. Soliven, Betty
Publisher StatementDissertation Summer 2011