The Role of Tau Phosphorylation in Diabetic Peripheral Neuropathy - Project Summary: Broad Impact: Diabetic peripheral neuropathy is a condition that affects millions of people worldwide. Here we propose a set of experiments that will determine the role of insulin dysregulation and tau phosphorylation by GSK3β in T1DM and diabetic peripheral neuropathy. We believe these experiments will lead to a breakthrough in our understanding of diabetic neuropathy that will impact development of new therapeutics for years to come. Specific aims: Based on previous publications and our preliminary data, we hypothesize that insulin deficiency in the STZ model will upregulate the activity of GSK3β and drive up the level of phosphorylated tau within the neurons of the sciatic nerve resulting in neural dysfunction, IENF loss and mechanical and thermal hypersensitivity. To test this hypothesis, we will first identify increases in tau phosphorylation and dysregulation of the insulin signaling pathway using high content microscopy and western blot techniques. Then, we will confirm the role of GSK3β in tau phosphorylation with a GSK3β specific inhibitor and TRPV1Cre x GSK3βFL mice. Last we will develop new in vivo and in vitro modeling systems using AAV vectors that can be used to examine the effects of GSK3β activation in the absence of the insulin dysregulation that accompany T1DM. Career development and goals: In order to provide further growth of Dr. James Nichols’ career, the K99 phase of this award will be focused on 1) additional training in specific research techniques (High Content Microscopy, AAV vector delivery and Cre/lox systems, etc.); 2) professional development through mentorship, scientific writing, grant writing and attendance of scientific meetings; and 3) education in the field of peripheral neuropathies through quarterly meetings between Dr. Nichols and his mentorship team, daily mentoring by Dr. Andrew Shepherd, and collaborative opportunities with other PIs in the Neuroimmunology Lab. Career goals: Dr. Nichols’ long term career goal is to become a professor at a college of veterinary medicine or a college of medicine, so he can continue his research in the field of neuropathic pain, continue to encourage medical students who wish to follow a career in research, and participate in the education of the next generations of medical students. Environment: The Laboratories of Neuroimmunology within the Department of Symptom Research at MD Anderson Cancer Center is comprised of over 40 scientists at various levels of their career ranging from Professors to student volunteers. This environment is perfect for collaborations with other labs and provides access to a plethora of core facilities to which the candidate has ready access. During the R00 phase of this award Dr. Nichols will seek a similarly equipped environment to continue his studies in neuropathic pain, and the development of therapies for DPN.
