Understanding neurite growth regulation remains a seminal problem in neurobiology. During development and regeneration, neurite growth is modulated by neurotrophin-activated signaling endosomes that transmit regulatory signals between soma and growth cones. After injury, delivering neurotrophic therapeutics to injured neurons is limited by our understanding of how signaling endosome localization in the growth cone affects neurite growth. Nanobiotechnology is providing new tools to answer previously inaccessible questions. Here, we show superparamagnetic nanoparticles (MNPs) functionalized with TrkB agonist antibodies are endocytosed into signaling endosomes by primary neurons that activate TrkB-dependent signaling, gene expression and promote neurite growth. These MNP signaling endosomes are trafficked into nascent and existing neurites and transported between somas and growth cones in vitro and in vivo. Manipulating MNP-signaling endosomes by a focal magnetic field alters growth cone motility and halts neurite growth in both peripheral and central nervous system neurons, demonstrating signaling endosome localization in the growth cone regulates motility and neurite growth. These data suggest functionalized MNPs may be used as a platform to study subcellular organelle localization and to deliver nanotherapeutics to treat injury or disease in the central nervous system. axon | nanotechnology C entral nervous system (CNS) neurons fail to regenerate after injury or disease because of reduced intrinsic axon growth ability (1, 2), inhibitory molecules (3-6), and deficient neurotrophic factor signaling (7-9). Neurotrophins, like brain-derived neurotrophic factor (BDNF), activate tropomyosin-related kinase B (TrkB) receptors and are endocytosed by clathrin-dependent and -independent mechanisms into signaling endosomes (10, 11). These signaling endosomes signal persistently during retrograde (12) and anterograde (13, 14) transport in axons or dendrites (15, 16) directing neurite growth, survival, and cell migration (17, 18). Signaling endosomes are critical long-range communication links used by neurons in the central and peripheral nervous system during development and regeneration (17), whose dysfunction is linked to nervous system disorders (19-21). Therefore, studying signaling endosome localization and related functions in regulating neurite growth is vital. MNPs are emerging as flexible, multimodal nanoparticles that can be targeted to specific tissues or cells by molecular functionalization. To alter signaling endosome localization, we targeted functionalized MNPs to active TrkB signaling endosomes and demonstrate that magnetically manipulating their localization affects growth cone behavior and neurite growth. ResultsTo load MNPs into TrkB signaling endosomes, 50-nm MNPs were functionalized with the anti-TrkB agonist antibody, 29D7, conjugated to Alexa 594. 29D7 activates TrkB and enhances retinal ganglion cell (RGC) survival and neurite growth in vitro and in vivo (22). Now, we show 29D7 facilitates rapid MNP e...

Th17 cells, and their related cytokines, are important inflammatory mediators in autoimmune uveitis. Animal and human studies continue to provide new information to direct development of new cytokine-targeted therapies for patients with uveitis.

These results support the hypothesis that mitochondria locally modulate signaling in the distal neurite and growth cone to affect the direction and the rate of neurite growth.

Together, these data support the hypothesis that intrinsic axon growth rate is regulated by an axon-specific growth program that differentially regulates growth cone motility.

Purpose: To perform a quantitative analysis of choriocapillaris (CC) flow deficits (FDs) in patients with uveitis. Design: Retrospective cross-sectional studyMethods: Swept-source optical coherence tomography based angiography (SS-OCTA) macular volume scans (3×3 mm and 6×6 mm) were obtained using the PLEX® Elite 9000: En face CC images were generated and analyzed using an automated flow deficit identification algorithm. Three quantitative metrics were determined for each eye: FD number (FDN), mean FD size (MFDS), and FD density (FDD). Quantitative metrics were compared between uveitis and control eyes. The uveitis cohort was further subdivided by the presence or absence of choroidal involvement, and quantitative metrics were compared between subgroups and normal controls Results: A total of 38 eyes from 38 controls and 73 eyes from 73 uveitis subjects were included in this study. Eyes with uveitis have significantly larger CC MFDS (3×3 mm, p<0.0001; 6×6 mm, p<0.0001) and higher FDD (p=0.0002; p=0.0076) when compared to control eyes. Additional analysis determined that these differences are due to the choroidal disease subgroup, which demonstrates significantly larger MFDS (3×3 =1108 μm 2 ; 6×6 =1104 μm 2 ) compared to both normal controls (752 μm 2 , p<0.0001; 802 μm 2 , p<0.0001) and uveitis patients without choroidal involvement (785 μm 2 , p<0.0001; 821 μm 2 , p<0.0001). No significant differences were found between the quantitative metrics of controls and patients without choroidal involvement.Conclusions: Automated quantification of CC can identify pathological FDs and provide quantitative metrics describing such lesions in patients with uveitis. Posterior uveitis patients have significantly larger CC FDs than patients with other forms of uveitis.