This series showcases video summaries of new findings published in the Journal of Clinical Investigation. This format allows authors to to provide a personally guided tour of their results and makes the research more accessible to a broad readership. The JCI accepts videos from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Mutations in the RAS oncogene are present in almost 25% of all cancers. Direct targeting of RAS for limiting these cancers has been challenging; therefore, elucidation of the pathways downstream of RAS has potential to provide therapeutic targets. In this episode, David Virshup and Jit Kong Cheong discuss their work, which identifies the serine/threonine kinase casein kinase 1a (CK1a) as a key negative regulator of oncogenic RAS-induced autophagy. Combined pharmacological inhibition of both CK1a and autophagy attenuated the growth of RAS-driven tumor xenografts. The results of this study support further exploration of CK1a as a therapeutic target for oncogenic RAS-driven cancers.
The inherited form of blindness retinitis pigmentosa (RP) results from a progressive loss of photoreceptors. RP-associated mutations directly promote the death of rod cells, which are required for vision in low light, and indirectly promote the subsequent degeneration of cone cells, which are necessary for daytime vision. While the mechanisms that mediate cone death are not fully understood, an increase in oxidative stress has been implicated in the degradation of these cells. In this episode, Connie Cepko and Wenjun Xiong detail their work, which shows that adeno-associated virus-mediated delivery of antioxidant genes prolongs photoreceptor survival and improves visual acuity in multiple murine RP models. The results of this study suggest that targeted delivery of antioxidant genes has potential to ameliorate other diseases characterized by oxidative stress-induced cell degradation.
Retinitis pigmentosa (RP) is an inherited degenerative eye disease that results from the presence of mutations in rod-associated genes. Cone cells, which mediate day light vision, also progressively degrade in RP; however, the mechanisms that mediate loss of these cells are not completely understood. In RP, dying cones exhibit signs of starvation, suggesting metabolic dysfunction in these cells. In this episode, Claudio Punzo and Aditya Venkatesh present their work, which demonstrates that constitutive activation of the metabolic regulator mTORC1 prolongs cone survival and maintains cone function in murine models of RP. The results of this study support further exploration of strategies to improve metabolic function for maintaining cone function in RP.
Synaptic plasticity, or the ability of synapses to strengthen or weaken connections, is thought to underlie learning and memory. In this episode, Erwin Van Meir, Donald Rainnie, and Yoland Smith discuss their work, which identifies brain-specific angiogenesis inhibitor-1 (BAI1) as a determinant of synaptic plasticity and hippocampal-dependent spatial learning and memory in mice. BAI1 prevents degradation the post-synaptic density component PSD-95, and restoration of PSD-95 in the BAI1-deficient hippocampal neurons ameliorated synaptic plasticity deficits. The results from this study provide insight into pathways that mediate spatial learning and memory, which are altered in several neurological diseases.
Cholangiocarcinoma is a cancer of the bile duct that has a poor prognosis, largely due to it being refractory to available therapies. In this episode, Stuart Forbes and Luke Bolter reveal that the canonical WNT signaling pathway drives cholangiocarcinoma growth by regulating epithelial cell proliferation. Inflammatory macrophages, which infiltrate the cancer, are a major source of the WNT-inducing signal and thereby facilitate cholangiocarcinoma growth. The results of this study support further investigation into the use of WNT inhibitors to treat cholangiocarcinoma.
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