Browsing by Author "Jin, Jing"

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Open Access
Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity.
(The Journal of clinical investigation, 2016-07) Souma, Tomokazu; Tompson, Stuart W; Thomson, Benjamin R; Siggs, Owen M; Kizhatil, Krishnakumar; Yamaguchi, Shinji; Feng, Liang; Limviphuvadh, Vachiranee; Whisenhunt, Kristina N; Maurer-Stroh, Sebastian; Yanovitch, Tammy L; Kalaydjieva, Luba; Azmanov, Dimitar N; Finzi, Simone; Mauri, Lucia; Javadiyan, Shahrbanou; Souzeau, Emmanuelle; Zhou, Tiger; Hewitt, Alex W; Kloss, Bethany; Burdon, Kathryn P; Mackey, David A; Allen, Keri F; Ruddle, Jonathan B; Lim, Sing-Hui; Rozen, Steve; Tran-Viet, Khanh-Nhat; Liu, Xiaorong; John, Simon; Wiggs, Janey L; Pasutto, Francesca; Craig, Jamie E; Jin, Jing; Quaggin, Susan E; Young, Terri L
Primary congenital glaucoma (PCG) is a devastating eye disease and an important cause of childhood blindness worldwide. In PCG, defects in the anterior chamber aqueous humor outflow structures of the eye result in elevated intraocular pressure (IOP); however, the genes and molecular mechanisms involved in the etiology of these defects have not been fully characterized. Previously, we observed PCG-like phenotypes in transgenic mice that lack functional angiopoietin-TEK signaling. Herein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function. Multiple cellular mechanisms were responsible for the loss of protein function resulting from individual TEK variants, including an absence of normal protein production, protein aggregate formation, enhanced proteasomal degradation, altered subcellular localization, and reduced responsiveness to ligand stimulation. Further, in mice, hemizygosity for Tek led to the formation of severely hypomorphic Schlemm's canal and trabecular meshwork, as well as elevated IOP, demonstrating that anterior chamber vascular development is sensitive to Tek gene dosage and the resulting decrease in angiopoietin-TEK signaling. Collectively, these results identify TEK mutations in patients with PCG that likely underlie disease and are transmitted in an autosomal dominant pattern with variable expressivity.
Open Access
Angiopoietin-1 is required for Schlemm's canal development in mice and humans.
(The Journal of clinical investigation, 2017-12) Thomson, Benjamin R; Souma, Tomokazu; Tompson, Stuart W; Onay, Tuncer; Kizhatil, Krishnakumar; Siggs, Owen M; Feng, Liang; Whisenhunt, Kristina N; Yanovitch, Tammy L; Kalaydjieva, Luba; Azmanov, Dimitar N; Finzi, Simone; Tanna, Christine E; Hewitt, Alex W; Mackey, David A; Bradfield, Yasmin S; Souzeau, Emmanuelle; Javadiyan, Shari; Wiggs, Janey L; Pasutto, Francesca; Liu, Xiaorong; John, Simon Wm; Craig, Jamie E; Jin, Jing; Young, Terri L; Quaggin, Susan E
Primary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm's canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development.
Open Access
Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP.
(Proceedings of the National Academy of Sciences of the United States of America, 2018-02) Souma, Tomokazu; Thomson, Benjamin R; Heinen, Stefan; Carota, Isabel Anna; Yamaguchi, Shinji; Onay, Tuncer; Liu, Pan; Ghosh, Asish K; Li, Chengjin; Eremina, Vera; Hong, Young-Kwon; Economides, Aris N; Vestweber, Dietmar; Peters, Kevin G; Jin, Jing; Quaggin, Susan E
The angiopoietin (ANGPT)-TIE2/TEK signaling pathway is essential for blood and lymphatic vascular homeostasis. ANGPT1 is a potent TIE2 activator, whereas ANGPT2 functions as a context-dependent agonist/antagonist. In disease, ANGPT2-mediated inhibition of TIE2 in blood vessels is linked to vascular leak, inflammation, and metastasis. Using conditional knockout studies in mice, we show TIE2 is predominantly activated by ANGPT1 in the cardiovascular system and by ANGPT2 in the lymphatic vasculature. Mechanisms underlying opposing actions of ANGPT2 in blood vs. lymphatic endothelium are poorly understood. Here we show the endothelial-specific phosphatase VEPTP (vascular endothelial protein tyrosine phosphatase) determines TIE2 response to ANGPT2. VEPTP is absent from lymphatic endothelium in mouse in vivo, permitting ANGPT2/TIE2-mediated lymphangiogenesis. Inhibition of VEPTP converts ANGPT2 into a potent TIE2 activator in blood endothelium. Our data support a model whereby VEPTP functions as a rheostat to modulate ANGPT2 ligand effect on TIE2.
Open Access
Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation.
(Kidney international, 2018-04-21) Liu, Pan; Wysocki, Jan; Souma, Tomokazu; Ye, Minghao; Ramirez, Veronica; Zhou, Bisheng; Wilsbacher, Lisa D; Quaggin, Susan E; Batlle, Daniel; Jin, Jing
Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that potently degrades angiotensin II to angiotensin 1-7. Previous studies showed that injection of the enzymatic ectodomain of recombinant ACE2 (rACE2) markedly increases circulatory levels of ACE2 activity, and effectively lowered blood pressure in angiotensin II-induced hypertension. However, due to the short plasma half-life of rACE2, its therapeutic potential for chronic use is limited. To circumvent this, we generated a chimeric fusion of rACE2 and the Ig fragment Fc segment to increase its plasma stability. This rACE2-Fc fusion protein retained full peptidase activity and exhibited greatly extended plasma half-life in mice, from less than two hours of the original rACE2, to over a week. A single 2.5 mg/kg injection of rACE2-Fc increased the overall angiotensin II-conversion activities in blood by up to 100-fold and enhanced blood pressure recovery from acute angiotensin II induced hypertension seven days after administration. To assess rACE2-Fc given weekly on cardiac protection, we performed studies in mice continuously infused with angiotensin II for 28 days and in a Renin transgenic mouse model of hypertension. The angiotensin II infused mice achieved sustained blood pressure control and reduced cardiac hypertrophy and fibrosis. In chronic hypertensive transgenic mice, weekly injections of rACE2-Fc effectively lowered plasma angiotensin II and blood pressure. Additionally, rACE2-Fc ameliorated albuminuria, and reduced kidney and cardiac fibrosis. Thus, our chimeric fusion strategy for rACE2-Fc is suitable for future development of new renin angiotensin system-based inhibition therapies.
Open Access
Observation of different tumor motion magnitude within liver and estimate of internal motion margins in postoperative patients with hepatocellular carcinoma.
(Cancer management and research, 2017-01) Zhao, Yu-Ting; Liu, Zhi-Kai; Wu, Qiu-Wen; Dai, Jian-Rong; Zhang, Tao; Jia, Angela Y; Jin, Jing; Wang, Shu-Lian; Li, Ye-Xiong; Wang, Wei-Hu
To assess motion magnitude in different parts of the liver through surgical clips in postoperative patients with hepatocellular carcinoma and to examine the correlation between the clip and diaphragm motion.Four-dimensional computed tomography images from 30 liver cancer patients under thermoplastic mask immobilization were selected for this study. Three to seven surgical clips were placed in the resection cavity of each patient. The liver volume on computed tomography image was divided into the right upper (RU), right middle (RM), right lower (RL), hilar, and left lobes. Agreement between the clip and diaphragm motion was assessed by calculating intraclass correlation coefficient, and Bland-Altman analysis (Diff). Furthermore, population-based and patient-specific margins for internal motion were evaluated.The clips located in the RU lobe showed the largest motion, (7.5±1.6) mm, which was significantly more than in the RM lobe (5.7±2.8 mm, p=0.019), RL lobe (4.8±3.3 mm, p=0.017), and hilar lobe (4.7±2.7 mm, p<0.001) in the cranial-caudal direction. The mean intraclass correlation coefficient values between the clip and diaphragm motion were 0.915, 0.735, 0.678, 0.670, and the mean Diff values between them were 0.1±0.8 mm, 2.3±1.4 mm, 3.1±2.0 mm, 2.4±1.5 mm, when clips were located in the RU lobe, RM lobe, RL lobe, and hilar lobe, respectively. The clip and diaphragm motions had high concordance when clips were located in the RU lobe. Internal margin can be reduced from 5 mm in the cranial-caudal direction based on patient population average and to 3 mm based on patient-specific margins.The motion magnitude of clips varied significantly depending on their location within the liver. The diaphragm was a more appropriate surrogate for tumor located in the RU lobe than for other lobes.
Open Access
SVEP1 as a Genetic Modifier of TEK-Related Primary Congenital Glaucoma.
(Investigative ophthalmology & visual science, 2020-10) Young, Terri L; Whisenhunt, Kristina N; Jin, Jing; LaMartina, Sarah M; Martin, Sean M; Souma, Tomokazu; Limviphuvadh, Vachiranee; Suri, Fatemeh; Souzeau, Emmanuelle; Zhang, Xue; Dan, Yongwook; Anagnos, Evie; Carmona, Susana; Jody, Nicole M; Stangel, Nickie; Higuchi, Emily C; Huang, Samuel J; Siggs, Owen M; Simões, Maria José; Lawson, Brendan M; Martin, Jacob S; Elahi, Elahe; Narooie-Nejad, Mehrnaz; Motlagh, Behzad Fallahi; Quaggin, Susan E; Potter, Heather D; Silva, Eduardo D; Craig, Jamie E; Egas, Conceição; Maroofian, Reza; Maurer-Stroh, Sebastian; Bradfield, Yasmin S; Tompson, Stuart W
Purpose:Affecting children by age 3, primary congenital glaucoma (PCG) can cause debilitating vision loss by the developmental impairment of aqueous drainage resulting in high intraocular pressure (IOP), globe enlargement, and optic neuropathy. TEK haploinsufficiency accounts for 5% of PCG in diverse populations, with low penetrance explained by variable dysgenesis of Schlemm's canal (SC) in mice. We report eight families with TEK-related PCG, and provide evidence for SVEP1 as a disease modifier in family 8 with a higher penetrance and severity. Methods:Exome sequencing identified coding/splice site variants with an allele frequency less than 0.0001 (gnomAD). TEK variant effects were assayed in construct-transfected HEK293 cells via detection of autophosphorylated (active) TEK protein. An enucleated eye from an affected member of family 8 was examined via histology. SVEP1 expression in developing outflow tissues was detected by immunofluorescent staining of 7-day mouse anterior segments. SVEP1 stimulation of TEK expression in human umbilical vascular endothelial cells (HUVECs) was measured by TaqMan quantitative PCR. Results:Heterozygous TEK loss-of-function alleles were identified in eight PCG families, with parent-child disease transmission observed in two pedigrees. Family 8 exhibited greater disease penetrance and severity, histology revealed absence of SC in one eye, and SVEP1:p.R997C was identified in four of the five affected individuals. During SC development, SVEP1 is secreted by surrounding tissues. SVEP1:p.R997C abrogates stimulation of TEK expression by HUVECs. Conclusions:We provide further evidence for PCG caused by TEK haploinsufficiency, affirm autosomal dominant inheritance in two pedigrees, and propose SVEP1 as a modifier of TEK expression during SC development, affecting disease penetrance and severity.