DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2014/0018338A1 Chandran Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2014/0018338A1 Chandran Et Al US 20140018338A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0018338A1 Chandran et al. (43) Pub. Date: Jan. 16, 2014 (54) METHODS AND ASSAYS FORTREATING CI2O 1/70 (2006.01) FLOVRIDAE INFECTIONS GOIN33/569 (2006.01) (52) U.S. Cl. (76) Inventors: Kartik Chandran, Brooklyn, NY (US); CPC .............. G0IN33/5035 (2013.01); C12O 1/70 Sean Whelan, Cambridge, MA (US); (2013.01); G0IN33/56983 (2013.01); A61 K Thijn Brummelkamp, Amsterdam 31/566 (2013.01); A61 K3I/55 (2013.01) (NL); Jan Carette, Palo Alto, CA (US); USPC ........... 514/178; 514/44. A 435/6.13:435/11; Matthijs Raaben, De Belt (NL) 435/7.92; 43.5/5: 514/217 (21) Appl. No.: 13/979,179 (57) ABSTRACT Methods and assays for treating a subject with a filovirus (22) PCT Filed: Jan. 24, 2012 infection using an agent that inhibits Niemann-Pick CI (NPCI), VPSII, VPSI6, VPSI8, VPS33A, VPS39, VPS41, (86) PCT NO.: PCT/US12A22349 BLOCISI, BLOCIS2, GNPTAB, PIKFYVE, ARHGAP23 or S371 (c)(1), FIG4. Methods for screening for an agent that treats and/or (2), (4) Date: Sep. 25, 2013 prevents infection of a subject with a filovirus, where the methods comprise determining whether the agent inhibits one Related U.S. Application Data or more of Niemann-Pick CI (NPCI), VPSII, VPSI6, VPSI8, VPS33A, VPS39, VPS41. BLOCISI, BLOCIS2, GNPTAB, (60) Provisional application No. 61/435,858, filed on Jan. PIKFYVE, ARHGAP23 or FIG4, wherein an agent that 25, 2011. inhibits one or more of NPCI, VPSII, VPSI6, VPSI8, VPS33A, VPS39, VPS41, BLOCISI, BLOCIS2, GNPTAB, Publication Classification PIKFYVE, ARHGAP23 or FIG4 is a candidate for treating and/or preventing an infection with a filovirus and wherein an (51) Int. C. agent that does not inhibit NPCI, VPSII, VPSI6, VPSI8, GOIN33/50 (2006.01) VPS33A. VPS39, VPS41, BLOCISI, BLOCIS2, GNPTAB, A6 IK3I/55 (2006.01) PIKFYVE, ARHGAP23 or FIG4 is not a candidate for treat A6 IK3I/566 (2006.01) ing and/or preventing an infection with a filovirus. Critical entry factors: & CTSB a HOPS complex NPC Patent Application Publication Jan. 16, 2014 Sheet 2 of 34 US 2014/0018338A1 b C 8 3.s s2 ------------------------------------AP CeS e 7 Control NPC 3 a Š VPS 116t g 5 VPS33AG VPS33A NPC167 4 : NPC1 GT2 ACTB is 3 WT VPS11GT VPS33A NPC G NPC GT2 . FIGURE 1 B-1D Patent Application Publication Jan. 16, 2014 Sheet 3 of 34 US 2014/0018338A1 Filipin Staining Virus infections rVSV-G rVSV-GP-EbOW Control FIGURE 2A Patent Application Publication Jan. 16, 2014 Sheet 4 of 34 US 2014/0018338A1 b s 7 2 Fibroblasts 5 WT 4 S NPC nut NPC2nut ... 3 S. 21. C 100 - - - s e- s ) rWSW-G sŠ rVSV-GP-Ebov i. "- O. O U18666A (uM) FIGURE 2B-2D Patent Application Publication Jan. 16, 2014 Sheet 5 of 34 US 2014/0018338A1 s 8 AP Cels a 7. Control S. 6 Š VRS1&T 5. $ WPS33AG NPC1&T 4 NPCGT2 $ 3. X t EBOV G cleaved) FIGURE 3A-3B Patent Application Publication Jan. 16, 2014 Sheet 6 of 34 US 2014/0018338A1 C ji" 3888& WSG WS33A'it NFO: Gi: 5 38 '' FIGURE 3C-3D Patent Application Publication Jan. 16, 2014 Sheet 7 of 34 US 2014/0018338A1 -- 234. 29 -o - - 24 as 72 96 i2O O 24 48 2 96 20 Hours post-infection Hours post-infection O. Ebow (Control) via:W (Control) O. Ebov (to drug) Marv (no drug) O Ebow (NPC) Marv (NPC1) O Ebov (U18666A) Marv (U18666A) FIGURE 4A-4B Patent Application Publication Jan. 16, 2014 Sheet 8 of 34 US 2014/0018338A1 Critical entry factors: CTSB HOPS complex NPC FIGURE 4C Patent Application Publication Jan. 16, 2014 Sheet 9 of 34 US 2014/0018338A1 FIGURE 5A Patent Application Publication Jan. 16, 2014 Sheet 10 of 34 US 2014/0018338A1 1a : 8 in '- 40 as 2 8, iOO S2 883 g 80 5 30 20 C. O s C O SO CO SO 100 virus concentration (MOI) FIGURE 5B-5C Patent Application Publication Jan. 16, 2014 Sheet 11 of 34 US 2014/0018338A1 HAP1 cells mutagenized with gene trap (complexity - 100x 106) unselected selected with Control - rWSW-GP-Ebola ( Y deep sequence deep sequence isolate insertion Sites insertion Sites cona derivatives l Count independent count independent functional insertions per gene insertions per gene Studies Control experimental dataSet dataSet -430,000 w -700 insertions insetors calculate per gene the significance of enrichment in experimental dataset gene with multiple insertions and high significance of Expected Observed enrichment (based on control) Genes in experimental dataset FIGURE 6 Patent Application Publication Jan. 16, 2014 Sheet 12 of 34 US 2014/0018338A1 pose WS syS s WS33Ak SNossos orSeŠsessessssssssssssssSssssssssssssssssssssssssssssssssssssssssssss S WPS1 endogenous locus PS11 gene trap ocus PS33 endogenous locus PS33 gene trap locus FIGURE 7A-7B Patent Application Publication Jan. 16, 2014 Sheet 13 of 34 US 2014/0018338A1 FIGURE 7C Patent Application Publication Jan. 16, 2014 Sheet 14 of 34 US 2014/0018338A1 8 b ii iss c --&N x\\ S 8 f 8 : & Ko S 7 C CHO cells d 6 NC g 5 W s 4. NPC10 g " 3 st CKai. S 2 J FIGURE 8A-8B Patent Application Publication Jan. 16, 2014 Sheet 15 of 34 US 2014/0018338A1 7. 6 $ $ $ $ Fibroblasts 5 Control 4. NPC2 muta CS& CX& cSS S. is FIGURE 9 Patent Application Publication Jan. 16, 2014 Sheet 16 of 34 US 2014/0018338A1 a. CHO-NPC10/vec CHO-NPC10/NPC1-flag S FIGURE 10A-10B Patent Application Publication Jan. 16, 2014 Sheet 17 of 34 US 2014/0018338A1 a. b g s 200 S 2 50 se 3 No drug SD 100 . g E-64 se < 50 e O s O SN && cS CN Š C V S (S NY N Q SksS CN S3 C C. S. C. S. CCatB hCatB- - CCat SC hCat on CCat C Š- Contoloadin FIGURE 11 A-11C Patent Application Publication Jan. 16, 2014 Sheet 18 of 34 US 2014/0018338A1 nOck BafA NHC FIGURE 12 Patent Application Publication Jan. 16, 2014 Sheet 19 of 34 US 2014/0018338A1 NPC GT2 FIGURE 13 Patent Application Publication Jan. 16, 2014 Sheet 20 of 34 US 2014/0018338A1 OO ::::::::: 10 :::::::: 8O n 8 60 m 6 No drug : CD 40 k As a A aS2 4 U18666A S S 20 2 h pi: 48 72 96 48 72 96 48 E.OV MarV MarV HUWEC OC FIGURE 14A-14B Patent Application Publication Jan. 16, 2014 Sheet 21 of 34 US 2014/0018338A1 6 DMSO vehicle 5 S. a was Š U 8666A 3 3 2 O Time of pretreatment (h) OO O so to so Time of U18666A addition (min) FIGURE 15A-15B Patent Application Publication Jan. 16, 2014 Sheet 22 of 34 US 2014/0018338A1 S irriprattireUntreated (88. s in * : S s wa se cy. S 30 . - - - - - is as hrs fairs 38 is irs Niarburg Cit? Exia airs SS FIGURE 16 Patent Application Publication Jan. 16, 2014 Sheet 23 of 34 US 2014/0018338A1 {} so EbOW 80 or ... 8 O 8 S ({} 3. 28 O { 2 3 4 S 8 8 & 3 : S. Of 3. 80 7 S SO 48 38 { 3 & S S 8 {} 2 3 4 Days post-chaenge Wid-type mice (NPC -f- O Knockout mice (NPC -f--) FIGURE 17A-17B Patent Application Publication Jan. 16, 2014 Sheet 24 of 34 US 2014/0018338A1 100 90 80 f &s is 60 8 st s imipramine 25 mg/kg s 40 & 8 . s imipramine 15 mg/kg 30 2 * PBS in 8 innipramie (35 mgsg PBS to imipramine (25 mg/kg) kas S. s * imipramine (15 mg/kg) imipramine 35 mg/kg 2 i s 8 2 is S Days Post infection FIGURE 18 Patent Application Publication Jan. 16, 2014 Sheet 25 of 34 US 2014/0018338A1 Steroi-binding NPC2-binding Cysteine-rich dorrain dorai tioai Erics a M finger (yopias sterol-sensing Flag contain tag FIGURE 19 Patent Application Publication Jan. 16, 2014 Sheet 26 of 34 US 2014/0018338A1 Filipin GP-EBOV GP-MARV staining None NPC1-flag s ; : . NPC1 AA-flag NPC AC-flag 2% NPC -A-flag FIGURE 20A-2OC Patent Application Publication Jan. 16, 2014 Sheet 27 of 34 US 2014/0018338A1 3. NPC1-Flag lysate WSV: q s C. C. NPC -Flag P: kg &s B: is S&S NPC -Flag b O 2 4. 6 8 Lysate (1x10 celled./well) FIGURE 21 A-21B Patent Application Publication Jan. 16, 2014 Sheet 28 of 34 US 2014/0018338A1 d 3 sa Š Š-ŠŠ & Š 2 Š Š rVSV-GP S rVSV-GP O 20 40 60 80 OO NPC1-flag (ng/well) FIGURE 21 C-21D Patent Application Publication Jan. 16, 2014 Sheet 29 of 34 US 2014/0018338A1 al Side b ex do air C S Sibie 5 s -Š s ...-- s ce ser S t rVSV-GP SECa C 3. O.5 S rVSV-GP. i. Soluble O.O Domain C O O 2O 30 40 Soluble domain C (ig/mL) s s rVSV-GP E 50- Š rVSV-GP. S s y y O &c....access assoor-Š do so Soluble domain C-flag (ug/ml) FIGURE 22A-22C Patent Application Publication Jan. 16, 2014 Sheet 30 of 34 US 2014/0018338A1 FIGURE 23A-23B Patent Application Publication Jan. 16, 2014 Sheet 31 of 34 US 2014/0018338A1 Erdosora liter Cytoplasm FIGURE 24A-24B Patent Application Publication Jan. 16, 2014 Sheet 32 of 34 US 2014/0018338A1 Compound 3 FIGURE 24C-24D Patent Application Publication Jan. 16, 2014 Sheet 33 of 34 US 2014/0018338A1 TPA 2 Ru(bpy),3.
Load more

Recommended publications
  • New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology
    Cancer Research and Treatment 2003;35(4):304-313 New Approaches to Functional Process Discovery in HPV 16-Associated Cervical Cancer Cells by Gene Ontology Yong-Wan Kim, Ph.D.1, Min-Je Suh, M.S.1, Jin-Sik Bae, M.S.1, Su Mi Bae, M.S.1, Joo Hee Yoon, M.D.2, Soo Young Hur, M.D.2, Jae Hoon Kim, M.D.2, Duck Young Ro, M.D.2, Joon Mo Lee, M.D.2, Sung Eun Namkoong, M.D.2, Chong Kook Kim, Ph.D.3 and Woong Shick Ahn, M.D.2 1Catholic Research Institutes of Medical Science, 2Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul; 3College of Pharmacy, Seoul National University, Seoul, Korea Purpose: This study utilized both mRNA differential significant genes of unknown function affected by the display and the Gene Ontology (GO) analysis to char- HPV-16-derived pathway. The GO analysis suggested that acterize the multiple interactions of a number of genes the cervical cancer cells underwent repression of the with gene expression profiles involved in the HPV-16- cancer-specific cell adhesive properties. Also, genes induced cervical carcinogenesis. belonging to DNA metabolism, such as DNA repair and Materials and Methods: mRNA differential displays, replication, were strongly down-regulated, whereas sig- with HPV-16 positive cervical cancer cell line (SiHa), and nificant increases were shown in the protein degradation normal human keratinocyte cell line (HaCaT) as a con- and synthesis. trol, were used. Each human gene has several biological Conclusion: The GO analysis can overcome the com- functions in the Gene Ontology; therefore, several func- plexity of the gene expression profile of the HPV-16- tions of each gene were chosen to establish a powerful associated pathway, identify several cancer-specific cel- cervical carcinogenesis pathway.
    [Show full text]
  • The Mouse Organellar Biogenesis Mutant Buff Results from a Mutation in Vps33a, a Homologue of Yeast Vps33 and Drosophila Carnation
    The mouse organellar biogenesis mutant buff results from a mutation in Vps33a, a homologue of yeast vps33 and Drosophila carnation Tamio Suzuki*†‡, Naoki Oiso*†, Rashi Gautam†§, Edward K. Novak§, Jean-Jacques Panthier¶, P. G. Suprabhaʈ, Thomas Vida**, Richard T. Swank§, and Richard A. Spritz*†† *Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, CO 80262; §Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263; ¶Institut National de la Recherche Agronomique, Ecole Nationale Ve´te´ rinaire d’Alfort, 94704 Maisons-Alfort Cedex, France; ʈCenter for Basic Neuroscience, University of Texas Southwestern, Dallas, TX 75390; and **Department of Microbiology and Molecular Genetics, University of Texas Medical School, Houston, TX 77030 Communicated by Theodore T. Puck, Eleanor Roosevelt Institute for Cancer Research, Denver, CO, December 2, 2002 (received for review July 16, 2002) In the mouse, more than 16 loci are associated with mutant bf-mutant Vps33a does not. These results establish murine bf as phenotypes that include defective pigmentation, aberrant target- a murine homologue to the yeast vps33 mutant and suggest ing of lysosomal enzymes, prolonged bleeding, and immunodefi- VPS33A as a candidate gene for some cases of human HPS. ciency, the result of defective biogenesis of cytoplasmic organelles: melanosomes, lysosomes, and various storage granules. Many of Materials and Methods these mouse mutants are homologous to the human Hermansky– Mice and Backcross. Mice carrying the spontaneous mutation bf on Pudlak syndrome (HPS), Chediak–Higashi syndrome, and Griscelli the C57BL͞6J strain were obtained from The Jackson Labora- syndrome. We have mapped and positionally cloned one of these tory and were subsequently bred at Roswell Park Cancer Insti- mouse loci, buff (bf), which has a mutant phenotype similar to that tute.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]
  • Supplementary Materials
    Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine
    [Show full text]
  • RNA-Seq Transcriptome Reveals Different Molecular Responses
    Zhao et al. BMC Genomics (2020) 21:475 https://doi.org/10.1186/s12864-020-06885-4 RESEARCH ARTICLE Open Access RNA-Seq transcriptome reveals different molecular responses during human and mouse oocyte maturation and fertilization Zheng-Hui Zhao1,2, Tie-Gang Meng1,3, Ang Li1, Heide Schatten4, Zhen-Bo Wang1,2* and Qing-Yuan Sun1,3* Abstract Background: Female infertility is a worldwide concern and the etiology of infertility has not been thoroughly demonstrated. Although the mouse is a good model system to perform functional studies, the differences between mouse and human also need to be considered. The objective of this study is to elucidate the different molecular mechanisms underlying oocyte maturation and fertilization between human and mouse. Results: A comparative transcriptome analysis was performed to identify the differentially expressed genes and associated biological processes between human and mouse oocytes. In total, 8513 common genes, as well as 15, 165 and 6126 uniquely expressed genes were detected in human and mouse MII oocytes, respectively. Additionally, the ratios of non-homologous genes in human and mouse MII oocytes were 37 and 8%, respectively. Functional categorization analysis of the human MII non-homologous genes revealed that cAMP-mediated signaling, sister chromatid cohesin, and cell recognition were the major enriched biological processes. Interestingly, we couldn’t detect any GO categories in mouse non-homologous genes. Conclusions: This study demonstrates that human and mouse oocytes exhibit significant differences in gene expression profiles during oocyte maturation, which probably deciphers the differential molecular responses to oocyte maturation and fertilization. The significant differences between human and mouse oocytes limit the generalizations from mouse to human oocyte maturation.
    [Show full text]
  • The Genetics of Bipolar Disorder
    Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF.
    [Show full text]
  • CORVET, CHEVI and HOPS – Multisubunit Tethers of the Endo
    © 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs189134. doi:10.1242/jcs.189134 REVIEW SUBJECT COLLECTION: CELL BIOLOGY AND DISEASE CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease Jan van der Beek‡, Caspar Jonker*,‡, Reini van der Welle, Nalan Liv and Judith Klumperman§ ABSTRACT contact between two opposing membranes and pull them close Multisubunit tethering complexes (MTCs) are multitasking hubs that together to allow interactions between SNARE proteins (Murray form a link between membrane fusion, organelle motility and signaling. et al., 2016). SNARE assembly then provides additional fusion CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. specificity and drives the actual fusion process (Ohya et al., 2009; They regulate the major membrane flows required for endocytosis, Stroupe et al., 2009). In this Review, we focus on the role of tethering lysosome biogenesis, autophagy and phagocytosis. In addition, proteins in endo-lysosomal fusion events. individual subunits control complex-independent transport of specific Tethering proteins can be divided into two main groups: long cargoes and exert functions beyond tethering, such as attachment to coiled-coil proteins (Gillingham and Munro, 2003) and microtubules and SNARE activation. Mutations in CHEVI subunits multisubunit tethering complexes (MTCs). MTCs form a lead to arthrogryposis, renal dysfunction and cholestasis (ARC) heterogenic group of protein complexes that consist of up to ten ∼ syndrome, while defects in CORVET and, particularly, HOPS are subunits resulting in a general length of 50 nm (Brocker et al., associated with neurodegeneration, pigmentation disorders, liver 2012; Chou et al., 2016; Hsu et al., 1998; Lürick et al., 2018; Ren malfunction and various forms of cancer.
    [Show full text]
  • Development of the Swimbladder Surfactant System and Biogenesis of Lysosome-Related Organelles Is Regulated by BLOS1 in Zebrafish
    | INVESTIGATION Development of the Swimbladder Surfactant System and Biogenesis of Lysosome-Related Organelles Is Regulated by BLOS1 in Zebrafish Tianbing Chen,*,† Guili Song,* Huihui Yang,*,† Lin Mao,*,† Zongbin Cui,*,1 and Kaiyao Huang*,1 *Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China and †University of Chinese Academy of Sciences, Beijing 100049, China ABSTRACT Hermansky-Pudlak syndrome (HPS) is a human autosomal recessive disorder that is characterized by oculocutaneous albinism and a deficiency of the platelet storage pool resulting from defective biogenesis of lysosome-related organelles (LROs). To date, 10 HPS genes have been identified, three of which belong to the octamer complex BLOC-1 (biogenesis of lysosome-related organelles complex 1). One subunit of the BLOC-1 complex, BLOS1, also participates in the BLOC-1-related complex (BORC). Due to lethality at the early embryo stage in BLOS1 knockout mice, the function of BLOS1 in the above two complexes and whether it has a novel function are unclear. Here, we generated three zebrafish mutant lines with a BLOC-1 deficiency, in which melanin and silver pigment formation was attenuated as a result of mutation of bloc1s1, bloc1s2, and dtnbp1a, suggesting that they function in the same complex. In addition, mutations of bloc1s1 and bloc1s2 caused an accumulation of clusters of lysosomal vesicles at the posterior part of the tectum, representing a BORC-specific function in zebrafish. Moreover, bloc1s1 is highly expressed in the swimbladder during postembryonic stages and is required for positively regulating the expression of the genes, which is known to govern surfactant production and lung development in mammals.
    [Show full text]
  • MUTED Antibody - C-Terminal Region (ARP63301 P050) Data Sheet
    MUTED antibody - C-terminal region (ARP63301_P050) Data Sheet Product Number ARP63301_P050 Product Name MUTED antibody - C-terminal region (ARP63301_P050) Size 50ug Gene Symbol BLOC1S5 Alias Symbols DKFZp686E2287; MU; MUTED Nucleotide Accession# NM_201280 Protein Size (# AA) 187 amino acids Molecular Weight 21kDa Product Format Lyophilized powder NCBI Gene Id 63915 Host Rabbit Clonality Polyclonal Official Gene Full Name Muted homolog (mouse) Gene Family BLOC1S This is a rabbit polyclonal antibody against MUTED. It was validated on Western Blot by Aviva Systems Biology. At Aviva Systems Biology we manufacture rabbit polyclonal antibodies on a large scale (200-1000 Description products/month) of high throughput manner. Our antibodies are peptide based and protein family oriented. We usually provide antibodies covering each member of a whole protein family of your interest. We also use our best efforts to provide you antibodies recognize various epitopes of a target protein. For availability of antibody needed for your experiment, please inquire (). Partner Proteins BLOC1S2,DTNBP1,BLOC1S1,BLOC1S2,CNO,DTNBP1,SNAPIN,BLOC1S2,BLOC1S3,DTNBP1,PLDN,SQS TM1,YOD1 This gene encodes a component of BLOC-1 (biogenesis of lysosome-related organelles complex 1). Components of this complex are involved in the biogenesis of organelles such as melanosomes and platelet- Description of Target dense granules. A mouse model for Hermansky-Pudlak Syndrome is mutated in the murine version of this gene. Alternative splicing results in multiple transcript variants. Read-through transcription exists between this gene and the upstream EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) gene, as well as with the downstream TXNDC5 (thioredoxin domain containing 5) gene.
    [Show full text]
  • S41467-019-09800-Y.Pdf
    ARTICLE https://doi.org/10.1038/s41467-019-09800-y OPEN Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling Gregory Segala 1, Marcela A. Bennesch1, Nastaran Mohammadi Ghahhari1, Deo Prakash Pandey1,3, Pablo C. Echeverria 1, François Karch 2, Robert K. Maeda2 & Didier Picard 1 1234567890():,; In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/ Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifi- cally demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18- mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination. 1 Département de Biologie Cellulaire, Université de Genève, Sciences III, 30 quai Ernest-Ansermet, 1211 Genève, Switzerland. 2 Département de Génétique et Évolution, Université de Genève, Sciences III, 30 quai Ernest-Ansermet,
    [Show full text]
  • The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy
    International Journal of Molecular Sciences Review The Impact of Transcription Factor Prospero Homeobox 1 on the Regulation of Thyroid Cancer Malignancy Magdalena Rudzi ´nska 1,2 and Barbara Czarnocka 1,* 1 Department of Biochemistry and Molecular Biology, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland; [email protected] 2 Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia * Correspondence: [email protected]; Tel.: +48-225693812; Fax: +48-225693712 Received: 7 April 2020; Accepted: 30 April 2020; Published: 2 May 2020 Abstract: Transcription factor Prospero homeobox 1 (PROX1) is continuously expressed in the lymphatic endothelial cells, playing an essential role in their differentiation. Many reports have shown that PROX1 is implicated in cancer development and acts as an oncoprotein or suppressor in a tissue-dependent manner. Additionally, the PROX1 expression in many types of tumors has prognostic significance and is associated with patient outcomes. In our previous experimental studies, we showed that PROX1 is present in the thyroid cancer (THC) cells of different origins and has a high impact on follicular thyroid cancer (FTC) phenotypes, regulating migration, invasion, focal adhesion, cytoskeleton reorganization, and angiogenesis. Herein, we discuss the PROX1 transcript and protein structures, the expression pattern of PROX1 in THC specimens, and its epigenetic regulation. Next, we emphasize the biological processes and genes regulated by PROX1 in CGTH-W-1 cells, derived from squamous cell carcinoma of the thyroid gland. Finally, we discuss the interaction of PROX1 with other lymphatic factors. In our review, we aimed to highlight the importance of vascular molecules in cancer development and provide an update on the functionality of PROX1 in THC biology regulation.
    [Show full text]