Browsing by Author "Sun, Yang"

Now showing 1 - 10 of 14
  • Thumbnail Image
    Item
    Author Correction: Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway
    (Nature Publishing Group, 2020-07-28) Chen, Sisi; Wang, Qiang; Yu, Hao; Capitano, Maegan L.; Vemula, Sasidhar; Nabinger, Sarah C.; Gao, Rui; Yao, Chonghua; Kobayashi, Michihiro; Geng, Zhuangzhuang; Fahey, Aidan; Henley, Danielle; Liu, Stephen Z.; Barajas, Sergio; Cai, Wenjie; Wolf, Eric R.; Ramdas, Baskar; Cai, Zhigang; Gao, Hongyu; Luo, Na; Sun, Yang; Wong, Terrence N.; Link, Daniel C.; Liu, Yunlong; Boswell, H. Scott; Mayo, Lindsey D.; Huang, Gang; Kapur, Reuben; Yoder, Mervin C.; Broxmeyer, Hal E.; Gao, Zhonghua; Liu, Yan; Biochemistry and Molecular Biology, School of Medicine
  • Thumbnail Image
    Item
    Cilia-associated wound repair mediated by IFT88 in retinal pigment epithelium
    (Springer Nature, 2023-05-21) Ning, Ke; Bhuckory, Mohajeet B.; Lo, Chien‑Hui; Sendayen, Brent E.; Kowal, Tia J.; Chen, Ming; Bansal, Ruchi; Chang, Kun‑Che; Vollrath, Douglas; Berbari, Nicolas F.; Mahajan, Vinit B.; Hu, Yang; Sun, Yang; Biology, School of Science
    Primary cilia are conserved organelles that integrate extracellular cues into intracellular signals and are critical for diverse processes, including cellular development and repair responses. Deficits in ciliary function cause multisystemic human diseases known as ciliopathies. In the eye, atrophy of the retinal pigment epithelium (RPE) is a common feature of many ciliopathies. However, the roles of RPE cilia in vivo remain poorly understood. In this study, we first found that mouse RPE cells only transiently form primary cilia. We then examined the RPE in the mouse model of Bardet-Biedl Syndrome 4 (BBS4), a ciliopathy associated with retinal degeneration in humans, and found that ciliation in BBS4 mutant RPE cells is disrupted early during development. Next, using a laser-induced injury model in vivo, we found that primary cilia in RPE reassemble in response to laser injury during RPE wound healing and then rapidly disassemble after the repair is completed. Finally, we demonstrated that RPE-specific depletion of primary cilia in a conditional mouse model of cilia loss promoted wound healing and enhanced cell proliferation. In summary, our data suggest that RPE cilia contribute to both retinal development and repair and provide insights into potential therapeutic targets for more common RPE degenerative diseases.
  • Thumbnail Image
    Item
    Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms
    (Association for Research in Vision and Ophthalmology, 2022) McDowell, Colleen M.; Kizhatil, Krishnakumar; Elliott, Michael H.; Overby, Darryl R.; van Batenburg-Sherwood, Joseph; Millar, J. Cameron; Kuehn, Markus H.; Zode, Gulab; Acott, Ted S.; Anderson, Michael G.; Bhattacharya, Sanjoy K.; Bertrand, Jacques A.; Borras, Terete; Bovenkamp, Diane E.; Cheng, Lin; Danias, John; De Ieso, Michael Lucio; Du, Yiqin; Faralli, Jennifer A.; Fuchshofer, Rudolf; Ganapathy, Preethi S.; Gong, Haiyan; Herberg, Samuel; Hernandez, Humberto; Humphries, Peter; John, Simon W.M.; Kaufman, Paul L.; Keller, Kate E.; Kelley, Mary J.; Kelly, Ruth A.; Krizaj, David; Kumar, Ajay; Leonard, Brian C.; Lieberman, Raquel L.; Liton, Paloma; Liu, Yutao; Liu, Katy C.; Lopez, Navita N.; Mao, Weiming; Mavlyutov, Timur; McDonnell, Fiona; McLellan, Gillian J.; Mzyk, Philip; Nartey, Andrews; Pasquale, Louis R.; Patel, Gaurang C.; Pattabiraman, Padmanabhan P.; Peters, Donna M.; Raghunathan, Vijaykrishna; Rao, Ponugoti Vasantha; Rayana, Naga; Raychaudhuri, Urmimala; Reina-Torres, Ester; Ren, Ruiyi; Rhee, Douglas; Chowdhury, Uttio Roy; Samples, John R.; Samples, E. Griffen; Sharif, Najam; Schuman, Joel S.; Sheffield, Val C.; Stevenson, Cooper H.; Soundararajan, Avinash; Subramanian, Preeti; Sugali, Chenna Kesavulu; Sun, Yang; Toris, Carol B.; Torrejon, Karen Y.; Vahabikashi, Amir; Vranka, Janice A.; Wang, Ting; Willoughby, Colin E.; Xin, Chen; Yun, Hongmin; Zhang, Hao F.; Fautsch, Michael P.; Tamm, Ernst R.; Clark, Abbot F.; Ethier, C. Ross; Stamer, W. Daniel; Ophthalmology, School of Medicine
    Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.
  • Thumbnail Image
    Item
    Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms
    (ARVO, 2022-02) McDowell, Colleen M.; Kizhatil, Krishnakumar; Elliott, Michael H.; Overby, Darryl R.; Van Batenburg-Sherwood, Joseph; Millar, J. Cameron; Kuehn, Markus H.; Zode, Gulab; Acott, Ted S.; Anderson, Michael G.; Bhattacharya, Sanjoy K.; Bertrand, Jacques A.; Borras, Terete; Bovenkamp, Diane E.; Cheng, Lin; Danias, John; De Ieso, Michael Lucio; Du, Yiqin; Faralli, Jennifer A.; Fuchshofer, Rudolf; Ganapathy, Preethi S.; Gong, Haiyan; Herberg, Samuel; Hernandez, Humberto; Humphries, Peter; John, Simon W. M.; Kaufman, Paul L.; Keller, Kate E.; Kelley, Mary J.; Kelly, Ruth A.; Krizaj, David; Kumar, Ajay; Leonard, Brian C.; Lieberman, Raquel L.; Liton, Paloma; Liu, Yutao; Liu, Katy C.; Lopez, Navita N.; Mao, Weiming; Mavlyutov, Timur; McDonnell, Fiona; McLellan, Gillian J.; Mzyk, Philip; Nartey, Andrews; Pasquale, Louis R.; Patel, Gaurang C.; Pattabiraman, Padmanabhan P.; Peters, Donna M.; Raghunathan, Vijaykrishna; Rao, Ponugoti Vasantha; Rayana, Naga; Raychaudhuri, Urmimala; Reina-Torres, Ester; Ren, Ruiyi; Rhee, Douglas; Chowdhury, Uttio Roy; Samples, John R.; Samples, E. Griffen; Sharif, Najam; Schuman, Joel S.; Sheffield, Val C.; Stevenson, Cooper H.; Soundararajan, Avinash; Subramanian, Preeti; Sugali, Chenna Kesavulu; Sun, Yang; Toris, Carol B.; Torrejon, Karen Y.; Vahabikashi, Amir; Vranka, Janice A.; Wang, Ting; Willoughby, Colin E.; Xin, Chen; Yun, Hongmin; Zhang, Hao F.; Fautsch, Michael P.; Tamm, Ernst R.; Clark, Abbot F.; Ethier, C. Ross; Stamer, W. Daniel; Ophthalmology, School of Medicine
    Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.
  • Thumbnail Image
    Item
    Consensus Recommendations for Studies of Outflow Facility and Intraocular Pressure Regulation Using Ex Vivo Perfusion Approaches
    (Association for Research in Vision and Ophthalmology, 2024) Acott, Ted S.; Fautsch, Michael P.; Mao, Weiming; Ethier, C. Ross; Huang, Alex S.; Kelley, Mary J.; Aga, Mini; Bhattacharya, Sanjoy K.; Borras, Terete; Bovenkamp, Diane; Chowdhury, Uttio Roy; Clark, Abbot F.; Dibas, Mohammed I.; Du, Yiqin; Elliott, Michael H.; Faralli, Jennifer A.; Gong, Haiyan; Herberg, Samuel; Johnstone, Murray A.; Kaufman, Paul L.; Keller, Kate E.; Kelly, Ruth A.; Krizaj, David; Kuehn, Markus H.; Li, Hoi Lam; Lieberman, Raquel; Lin, Shan C.; Liu, Yutao; McDonnell, Fiona S.; McDowell, Colleen M.; McLellan, Gillian J.; Mzyk, Philip; Nair, Kayarat Saidas; Overby, Darryl R.; Peters, Donna M.; Raghunathan, VijayKrishna; Rao, Ponugoti Vasantha; Roddy, Gavin W.; Sharif, Najam A.; Shim, Myoung Sup; Sun, Yang; Thomson, Benjamin R.; Toris, Carol B.; Willoughby, Colin E.; Zhang, Hao F.; Freddo, Thomas F.; Fuchshofer, Rudolf; Hill, Kamisha R.; Karimi, Alireza; Kizhatil, Krishnakumar; Kopcyznski, Casey C.; Liton, Paloma; Patel, Gaurang; Peng, Michael; Pattabiraman, Padmanabhan P.; Prasanna, Ganesh; Reina-Torres, Ester; Samples, E. Griffen; Samples, John R.; Steel, Cynthia L.; Strohmaier, Clemens A.; Subramanian, Preeti; Sugali, Chenna Kesavulu; van Batenburg-Sherwood, Joseph; Wong, Cydney; Youngblood, Hannah; Zode, Gulab S.; White, Elizabeth; Stamer, W. Daniel; Ophthalmology, School of Medicine
    Intraocular pressure (IOP) elevation is the primary risk factor and currently the main treatable factor for progression of glaucomatous optic neuropathy. In addition to direct clinical and living animal in vivo studies, ex vivo perfusion of anterior segments and whole eyes is a key technique for studying conventional outflow function as it is responsible for IOP regulation. We present well-tested experimental details, protocols, considerations, advantages, and limitations of several ex vivo model systems for studying IOP regulation. These include: (1) perfused whole globes, (2) stationary anterior segment organ culture, (3) perfused human anterior segment organ culture, (4) perfused animal anterior segment organ culture, (5) perfused human corneal rims, and (6) perfused human anterior segment wedges. These methods, with due consideration paid to their strengths and limitations, comprise a set of very strong tools for extending our understanding of IOP regulation.
  • Thumbnail Image
    Item
    Defective INPP5E distribution in NPHP1‐related Senior–Loken syndrome
    (Wiley, 2021-01) Ning, Ke; Song, Emilie; Sendayen, Brent E.; Prosseda, Philipp P.; Chang, Kun-Che; Ghaffarieh, Alireza; Alvarado, Jorge A.; Wang, Biao; Haider, Kathryn M.; Berbari, Nicolas F.; Hu, Yang; Sun, Yang; Ophthalmology, School of Medicine
    Background: Senior-Loken syndrome is a rare genetic disorder that presents with nephronophthisis and retinal degeneration, leading to end-stage renal disease and progressive blindness. The most frequent cause of juvenile nephronophthisis is a mutation in the nephronophthisis type 1 (NPHP1) gene. NPHP1 encodes the protein nephrocystin-1, which functions at the transition zone (TZ) of primary cilia. Methods: We report a 9-year-old Senior-Loken syndrome boy with NPHP1 deletion, who presents with bilateral vision decrease and cystic renal disease. Renal function deteriorated to require bilateral nephrectomy and renal transplant. We performed immunohistochemistry, H&E staining, and electron microscopy on the renal sample to determine the subcellular distribution of ciliary proteins in the absence of NPHP1. Results: Immunohistochemistry and electron microscopy of the resected kidney showed disorganized cystic structures with loss of cilia in renal tubules. Phosphoinositides have been recently recognized as critical components of the ciliary membrane and immunostaining of kidney sections for phosphoinositide 5-phosphatase, INPP5E, showed loss of staining compared to healthy control. Ophthalmic examination showed decreased electroretinogram consistent with early retinal degeneration. Conclusion: The decreased expression of INPP5E specifically in the primary cilium, coupled with disorganized cilia morphology, suggests a novel role of NPHP1 that it is involved in regulating ciliary phosphoinositide composition in the ciliary membrane of renal tubular cells.
  • Thumbnail Image
    Item
    Distribution of Prototypical Primary Cilia Markers in Subtypes of Retinal Ganglion Cells
    (Wiley, 2022) Kowal, Tia J.; Dhande, Onkar S.; Wang, Biao; Wang, Qing; Ning, Ke; Liu, Wendy; Berbari, Nicolas F.; Hu, Yang; Sun, Yang; Biology, School of Science
    Loss of retinal ganglion cells (RGCs) underlies several forms of retinal disease including glaucomatous optic neuropathy, a leading cause of irreversible blindness. Several rare genetic disorders associated with cilia dysfunction have retinal degeneration as a clinical hallmark. Much of the focus of ciliopathy associated blindness is on the connecting cilium of photoreceptors; however, RGCs also possess primary cilia. It is unclear what roles RGC cilia play, what proteins and signaling machinery localize to RGC cilia, or how RGC cilia are differentiated across the subtypes of RGCs. To better understand these questions, we assessed the presence or absence of a prototypical cilia marker Arl13b and a widely distributed neuronal cilia marker AC3 in different subtypes of mouse RGCs. Interestingly, not all RGC subtype cilia are the same and there are significant differences even among these standard cilia markers. Alpha-RGCs positive for osteopontin, calretinin and SMI32 primarily possess AC3 positive cilia. Directionally selective RGCs that are CART positive or Trhr positive localize either Arl13b or AC3, respectively in cilia. Intrinsically photosensitive RGCs differentially localize Arl13b and AC3 based on melanopsin expression. Taken together, we characterized the localization of gold standard cilia markers in different subtypes of RGCs and conclude that cilia within RGC subtypes may be differentially organized. Future studies aimed at understanding RGC cilia function will require a fundamental ability to observe the cilia across subtypes as their signaling protein composition is elucidated. A comprehensive understanding of RGC cilia may reveal opportunities to understanding how their dysfunction leads to retinal degeneration.
  • Thumbnail Image
    Item
    Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography
    (Lippincott, Williams & Wilkins, 2018-03) Alvarado, Jorge A.; Srivastava, Vinita; Sun, Yang; Medicine, School of Medicine
    PURPOSE: To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT). PATIENTS AND METHODS: Fifteen TS in 11 patients diagnosed with primary open-angle, neovascular, aphakic, and uveitic glaucomas. Both Ahmed (n=11) and Baerveldt (n=4) TS were examined with 5-line raster anterior segment SD-OCT imaging. RESULTS: The exposed tubes of 2 patients had highly reflective intraluminal deposits in the corresponding exposed areas. Seven tubes without exposure had a thin rim of highly reflective material. Six tubes were clear of luminal deposits. The most common diagnosis in the study was uveitic glaucoma which occurred in 5 of the 15 eyes (33%). The next most common diagnosis was primary open-angle glaucoma which occurred in 4 of the 15 eyes (25%). There were 2 nonvalved Baerveldt tubes in each group. The mean duration of TS implantation was 15.0 months in the deposit group and 33.7 months in the group without luminal deposits. The majority of patients in each group were using eye drops at presentation (88.9% deposit, 83.3% clear), and the average intraocular pressure was 20.2 mm Hg in the deposit group and 19.0 mm Hg in the clear group. CONCLUSIONS: Anterior segment OCT imaging may be used to evaluate TS integrity. Intraluminal deposits in TS may occur as a natural response to implanted drainage device, possibly as an inflammatory response.
  • Thumbnail Image
    Item
    Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome
    (The Company of Biologists, 2017-10-15) Prosseda, Philipp P.; Luo, Na; Wang, Biao; Alvarado, Jorge A.; Hu, Yang; Sun, Yang; Ophthalmology, School of Medicine
    Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P2, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.
  • Thumbnail Image
    Item
    Mouse γ-Synuclein Promoter-Mediated Gene Expression and Editing in Mammalian Retinal Ganglion Cells
    (SfN, 2020-05-13) Wang, Qizhao; Zhuang, Pei; Huang, Haoliang; Li, Liang; Liu, Liang; Webber, Hannah C.; Dalal, Roopa; Siew, Leonard; Fligor, Clarisse M.; Chang, Kun-Che; Nahmou, Michael; Kreymerman, Alexander; Sun, Yang; Meyer, Jason S.; Goldberg, Jeffrey Louis; Hu, Yang; Biology, School of Science
    Optic neuropathies are a group of optic nerve (ON) diseases caused by various insults including glaucoma, inflammation, ischemia, trauma, and genetic deficits, which are characterized by retinal ganglion cell (RGC) death and ON degeneration. An increasing number of genes involved in RGC intrinsic signaling have been found to be promising neural repair targets that can potentially be modulated directly by gene therapy, if we can achieve RGC specific gene targeting. To address this challenge, we first used adeno-associated virus (AAV)-mediated gene transfer to perform a low-throughput in vivo screening in both male and female mouse eyes and identified the mouse γ-synuclein (mSncg) promoter, which specifically and potently sustained transgene expression in mouse RGCs and also works in human RGCs. We further demonstrated that gene therapy that combines AAV-mSncg promoter with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing can knock down pro-degenerative genes in RGCs and provide effective neuroprotection in optic neuropathies.SIGNIFICANCE STATEMENT Here, we present an RGC-specific promoter, mouse γ-synuclein (mSncg) promoter, and perform extensive characterization and proof-of-concept studies of mSncg promoter-mediated gene expression and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing in RGCs in vivo To our knowledge, this is the first report demonstrating in vivo neuroprotection of injured RGCs and optic nerve (ON) by AAV-mediated CRISPR/Cas9 inhibition of genes that are critical for neurodegeneration. It represents a powerful tool to achieve RGC-specific gene modulation, and also opens up a promising gene therapy strategy for optic neuropathies, the most common form of eye diseases that cause irreversible blindness.