Mentorship and investment in early-career researchers pays off
Recent research published in Nature Communications offers new insights into the genetics of inherited neuropathy and Charcot Marie Tooth (CMT) disease, a degenerative nerve disease that usually manifests with weakness and sensation loss in the feet and hands. Lead author Brett McCray, MD, PhD, from Johns Hopkins Medicine and his colleagues identified the small GTPase RhoA as a novel binding partner for TRPV4 and found that neuropathy mutations in TRPV4 completely disrupted RhoA binding.
McCray is a former fellow with the Inherited Neuropathy Consortium (INC) and lead author on the study, which focused on the mechanisms by which mutations in the ion channel TRPV4 lead to inherited neuropathy. A mutation in any of well over 50 genes can lead to CMT; mutations in TRPV4 have been associated with CMT type 2C.
“These findings are significant because RhoA is a master regulator of changes in the cytoskeleton and is integral to many processes affecting the nervous system, from axonal regeneration to the regulation of the blood-brain-barrier,” notes McCray. He explains that TRPV4 disease mutations result in increased RhoA activation. His lab found inhibition of RhoA could reverse neurodegeneration in a fly model of TRPV4. Together, all this suggests the effects of TRPV4 on RhoA signaling could be significant for conditions beyond TRPV4 neuropathy and extend to a diverse range of conditions in which RhoA is known to be over-activated.
“Our recent work suggests that excessive TRPV4 and RhoA activation might contribute to neuronal degeneration in a variety of situations,” he continues. His lab is currently investigating whether modulating TRPV4 and RhoA activity in animal models could have an impact on other conditions including traumatic and toxic nerve injury and other forms of inherited neuropathy.
One key for advancing medical research on rare diseases in this way is attracting and developing talented early-stage investigators like McCray, who initially found himself drawn to the study of human genetic disease because such research “has the potential to tell us a great deal about the genes and pathways that are essential for keeping us healthy.” He points out “some amazing mentors in the Charcot Marie Tooth field early in my career” sparked a lasting interest in rare disease study.
McCray received a two-year INC fellowship as he joined the neurology faculty at Johns Hopkins University. There, he developed a network of colleagues around the globe and learned to direct his penchant for basic science toward a more translational focus. INC’s training fellowship is geared toward physicians who have completed neurology residency and, like McCray, aspire to develop a clinical or laboratory research interest in hereditary neuropathies.
The fellowship offers broad training in clinical research in inherited neuropathies and a chance to conduct a more detailed research project.
McCray’s lab is pursuing the possibility of using TRPV4 antagonist drugs in patients with TRPV4 neuropathy and working with the INC to create a TRPV4 neuropathy patient database. This will allow for natural history studies, evaluation of potential biomarkers of disease progression, and, McCray hopes, eventually lead to a clinical trial in TRPV4 neuropathy.
For patients with rare diseases, and physicians and researchers dedicated to their conditions, investing in the early careers of research physicians offers the promise of deeper understanding of disease and possible treatment. Early-stage investigators looking to make their mark get their chance through scholar awards that act like a beacon, drawing talent to this important work.
The early phase of building a research program is intense and deeply challenging, notes McCray. “I’ve learned that being successful cannot happen without significant support and help,” he says.
The Inherited Neuropathy Consortium (INC) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Office of Rare Diseases Research (ORDR). INC is funded under grant number U54NS065712 as a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). All RDCRN consortia are supported by the network’s Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and NINDS.