? ? The Candidate, Dr. Fred Robinson, has been training for the last four years as a fellow in the laboratory of Dr. Jack Dixon. Dr. Dixon's Laboratory is in the Department of Pharmacology at the University of California San Diego (UCSD) School of Medicine. UCSD is a renowned research institution, particularly strong in the fields of neuroscience, signal transduction and cancer biology. Dr. Dixon is a world leader in the study of protein and lipid phosphatases. The Candidate has established a fledgling research program focused on understanding how mutations in myotubularin family phosphoinositide (PI) 3-phosphatases lead to Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT is the most common inherited neurological disorder, affecting about 1 in 2000 in the United States. CMT causes progressive degeneration of the muscles of the extremities and loss of sensory function. Type 4B CMT (CMT4B) is a severe form of the disease in which the myelin sheaths of peripheral nerves are abnormal. Mutations in the genes for either myotubularin related protein 2 (MTMR2) or MTMR13 cause CMT4B. The Candidate recently demonstrated that the MTMR2 and MTMR13 PI 3-phosphatases form a membrane-associated complex capable of regulating 3-phosphoinositides. As loss of either MTMR2 or MTMR13 is sufficient to cause CMT4B, MTMR13 is likely an essential regulator of MTMR2. To further probe the relationship between MTMR2 and MTMR13, the Candidate has generated Mtmrl 3-deficient mice.
The specific aims of the proposal are (1) Validate Mtmrl 3-deficient mice as a model of CMT4B disease, (2) Examine the impact of loss of Mtmrl 3 on Mtmr2 function, and (3) Determine how 3-phosphoinositide homeostasis and endosomal-lysosomal trafficking are perturbed in Mtmrl 3-deficient Schwann cells. Understanding how the Schwann cell endosomal-lysosomal pathway is altered by the dysregulation of 3- phosphoinositides may allow us to consider pharmacological modulation of the pathway as a therapeutic strategy. ? The initial phase of the work (1-2 years) will be carried under Dr. Dixon's supervision. The Candidate will also be mentored by Dr. Katerina Akassoglou, an expert in peripheral nerve biology and demyelination. This phase will focus on characterization of Mtmrl 3-deficient mice and on other aspects of the project for which key training is available at UCSD. Later, as an independent investigator, the Candidate will continue studying Mtmrl 3-deficient mice, focusing more specifically on Schwann cell biology. ? ? ?
| Logan, Anne M; Mammel, Anna E; Robinson, Danielle C et al. (2017) Schwann cell-specific deletion of the endosomal PI 3-kinase Vps34 leads to delayed radial sorting of axons, arrested myelination, and abnormal ErbB2-ErbB3 tyrosine kinase signaling. Glia 65:1452-1470 |
| Ng, Aubree A; Logan, Anne M; Schmidt, Eric J et al. (2013) The CMT4B disease-causing phosphatases Mtmr2 and Mtmr13 localize to the Schwann cell cytoplasm and endomembrane compartments, where they depend upon each other to achieve wild-type levels of protein expression. Hum Mol Genet 22:1493-506 |
| Robinson, Fred L; Niesman, Ingrid R; Beiswenger, Kristina K et al. (2008) Loss of the inactive myotubularin-related phosphatase Mtmr13 leads to a Charcot-Marie-Tooth 4B2-like peripheral neuropathy in mice. Proc Natl Acad Sci U S A 105:4916-21 |
