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28 results on '"Wu, J.C."'

8. A comprehensive TALEN-based knockout library for generating human induced pluripotent stem cell-based models for cardiovascular diseases

Author

Karakikes, I., Termglinchan, V., Cepeda, D.A., Lee, J., Diecke, S., Hendel, A., Itzhaki, I., Ameen, M., Shrestha, R., Wu, H., Ma, N., Shao, N.Y., Seeger, T., Woo, N.A., Wilson, K.D., Matsa, E., Porteus, M.H., Sebastiano, V., and Wu, J.C.

Subjects
Technology Platforms
Abstract

Rationale: Targeted genetic engineering using programmable nucleases such as transcription activator-like effector nucleases (TALENs) is a valuable tool for precise, site-specific genetic modification in the human genome. Objective: The emergence of novel technologies such as human induced pluripotent stem cells (iPSCs) and nuclease-mediated genome editing represent a unique opportunity for studying cardiovascular diseases in vitro. Methods and Results: By incorporating extensive literature and database searches, we designed a collection of TALEN constructs to knockout (KO) eighty-eight human genes that are associated with cardiomyopathies and congenital heart diseases. The TALEN pairs were designed to induce double-strand DNA break near the starting codon of each gene that either disrupted the start codon or introduced a frameshift mutation in the early coding region, ensuring faithful gene KO. We observed that all the constructs were active and disrupted the target locus at high frequencies. To illustrate the general utility of the TALEN-mediated KO technique, six individual genes (TNNT2, LMNA/C, TBX5, MYH7, ANKRD1, and NKX2.5) were knocked out with high efficiency and specificity in human iPSCs. By selectively targeting a dilated cardiomyopathy (DCM)-causing mutation (TNNT2 p.R173W) in patient-specific iPSC-derived cardiac myocytes (iPSC-CMs), we demonstrated that the KO strategy ameliorates the DCM phenotype in vitro. In addition, we modeled the Holt-Oram syndrome (HOS) in iPSC-CMs in vitro and uncovered novel pathways regulated by TBX5 in human cardiac myocyte development. Conclusions: Collectively, our study illustrates the powerful combination of iPSCs and genome editing technology for understanding the biological function of genes and the pathological significance of genetic variants in human cardiovascular diseases. The methods, strategies, constructs and iPSC lines developed in this study provide a validated, readily available resource for cardiovascular research.

Published
2017

9. Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Author

Cheng, H., Dharmadhikari, A.V., Varland, S., Ma, N., Domingo, D., Kleyner, R., Rope, A.F., Yoon, M., Stray-Pedersen, A., Posey, J.E., Crews, S.R., Eldomery, M.K., Akdemir, Z.C., Lewis, A.M., Sutton, V.R., Rosenfeld, J.A., Conboy, E., Agre, K., Xia, F., Walkiewicz, M., Longoni, M., High, F.A., Slegtenhorst, M.A. van, Mancini, G.M.S., Finnila, C.R., Haeringen, A. van, Hollander, N. den, Ruivenkamp, C., Naidu, S., Mahida, S., Palmer, E.E., Murray, L., Lim, D., Jayakar, P., Parker, M.J., Giusto, S., Stracuzzi, E., Romano, C, Beighley, J.S., Bernier, R.A., Kury, S., Nizon, M., Corbett, M.A., Shaw, M., Gardner, A., Barnett, C., Armstrong, R., Kassahn, K.S., Dijck, A. Van, Vandeweyer, G., Kleefstra, T., Schieving, J.H., Jongmans, M.C., Vries, B.B.A. de, Pfundt, R.P., Kerr, B., Rojas, S.K., Boycott, K.M., Person, R., Willaert, R., Eichler, E.E., Kooy, R.F., Yang, Y., Wu, J.C., Lupski, J.R., Arnesen, T., Cooper, G.M., Chung, W.K., Gecz, J., Stessman, H.A.F., Meng, L., Lyon, G.J., Cheng, H., Dharmadhikari, A.V., Varland, S., Ma, N., Domingo, D., Kleyner, R., Rope, A.F., Yoon, M., Stray-Pedersen, A., Posey, J.E., Crews, S.R., Eldomery, M.K., Akdemir, Z.C., Lewis, A.M., Sutton, V.R., Rosenfeld, J.A., Conboy, E., Agre, K., Xia, F., Walkiewicz, M., Longoni, M., High, F.A., Slegtenhorst, M.A. van, Mancini, G.M.S., Finnila, C.R., Haeringen, A. van, Hollander, N. den, Ruivenkamp, C., Naidu, S., Mahida, S., Palmer, E.E., Murray, L., Lim, D., Jayakar, P., Parker, M.J., Giusto, S., Stracuzzi, E., Romano, C, Beighley, J.S., Bernier, R.A., Kury, S., Nizon, M., Corbett, M.A., Shaw, M., Gardner, A., Barnett, C., Armstrong, R., Kassahn, K.S., Dijck, A. Van, Vandeweyer, G., Kleefstra, T., Schieving, J.H., Jongmans, M.C., Vries, B.B.A. de, Pfundt, R.P., Kerr, B., Rojas, S.K., Boycott, K.M., Person, R., Willaert, R., Eichler, E.E., Kooy, R.F., Yang, Y., Wu, J.C., Lupski, J.R., Arnesen, T., Cooper, G.M., Chung, W.K., Gecz, J., Stessman, H.A.F., Meng, L., and Lyon, G.J.

Abstract

Item does not contain fulltext, N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.

Published
2018

13. Reprogramming and transdifferentiation for cardiovascular development and regenerative medicine: where do we stand?

Author

Ebert, A.D., Diecke, S., Chen, I.Y., and Wu, J.C.

Subjects
Technology Platforms
Abstract

Heart disease remains a leading cause of mortality and a major worldwide healthcare burden. Recent advances in stem cell biology have made it feasible to derive large quantities of cardiomyocytes for disease modeling, drug development, and regenerative medicine. The discoveries of reprogramming and transdifferentiation as novel biological processes have significantly contributed to this paradigm. This review surveys the means by which reprogramming and transdifferentiation can be employed to generate induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and induced cardiomyocytes (iCMs). The application of these patient-specific cardiomyocytes for both in vitro disease modeling and in vivo therapies for various cardiovascular diseases will also be discussed. We propose that, with additional refinement, human disease-specific cardiomyocytes will allow us to significantly advance the understanding of cardiovascular disease mechanisms and accelerate the development of novel therapeutic options.

Published
2015

14. Global position paper on cardiovascular regenerative medicine

Author

Fernández-Avilés, F. (Francisco), Sanz-Ruiz, R. (Ricardo), Climent, A.M. (Andreu M.), Badimon, L. (Lina), Bolli, R. (Roberto), Charron, D. (Dominique), Fuster, V. (Valentin), Janssens, S. (Stefan), Kastrup, J. (Jens), Kim, H.-S. (Hyo-Soo), Lüscher, T.F., Martin, J.F. (John F.), Menasche, P. (Philippe), Simari, P. (Patricio), Stone, G.W. (Gregg), Terzic, A. (Andre), Willerson, J.T. (James), Wu, J.C. (Joseph C.), Joseph, C.W. (C. Wu), Broughton, K. (Kathleen), DiFede, D.L. (Darcy L.), Dimmeler, S. (Stefanie), Madonna, R. (Rosalinda), Penn, M.S. (Marc S.), Sussman, M.A. (Mark A.), Sluijter, J.P.G., Woller, K.C. (Kai C.), Balkan, W. (Wayne), Chamuleau, S.A.J. (Steven), Fernández-Santos, M.E. (Maria Eugenia), Goliasch, G. (Georg), Gyöngyösi, M. (Mariann), Hare, J.M. (Joshua M.), Tompkins, B.A. (Bryon A.), Winkler, J. (Johannes), Bayés-Genis, A. (Antoni), Henry, T.D. (Timothy), Taylor, D.A. (Doris), Lerman, A. (Amir), Pelacho, B. (Beatriz), Prosper, F. (Felipe), Perin, E.C. (Emerson ), Pompilio, G. (Giulio), Gersh, B.J. (Bernard), Bartúnek, J. (Jozef), Duckers, E. (Eric), Ferdinandy, P. (Péter), Losordo, D.W. (Douglas W.), Čanchez, P.L. (Pedro L.), Sherman, W. (Warren), Wojakowski, W. (Wojtek), Zeiher, A.M. (Andreas), Roncalli, J. (Jérôme), Mathur, A. (Anthony), Crea, F. (Filippo), D'Amario, D. (Domenico), Povsic, T.J. (Thomas J.), Traverse, J.H. (Jay), Ylä-Herttuala, S. (Seppo), Fernández-Avilés, F. (Francisco), Sanz-Ruiz, R. (Ricardo), Climent, A.M. (Andreu M.), Badimon, L. (Lina), Bolli, R. (Roberto), Charron, D. (Dominique), Fuster, V. (Valentin), Janssens, S. (Stefan), Kastrup, J. (Jens), Kim, H.-S. (Hyo-Soo), Lüscher, T.F., Martin, J.F. (John F.), Menasche, P. (Philippe), Simari, P. (Patricio), Stone, G.W. (Gregg), Terzic, A. (Andre), Willerson, J.T. (James), Wu, J.C. (Joseph C.), Joseph, C.W. (C. Wu), Broughton, K. (Kathleen), DiFede, D.L. (Darcy L.), Dimmeler, S. (Stefanie), Madonna, R. (Rosalinda), Penn, M.S. (Marc S.), Sussman, M.A. (Mark A.), Sluijter, J.P.G., Woller, K.C. (Kai C.), Balkan, W. (Wayne), Chamuleau, S.A.J. (Steven), Fernández-Santos, M.E. (Maria Eugenia), Goliasch, G. (Georg), Gyöngyösi, M. (Mariann), Hare, J.M. (Joshua M.), Tompkins, B.A. (Bryon A.), Winkler, J. (Johannes), Bayés-Genis, A. (Antoni), Henry, T.D. (Timothy), Taylor, D.A. (Doris), Lerman, A. (Amir), Pelacho, B. (Beatriz), Prosper, F. (Felipe), Perin, E.C. (Emerson ), Pompilio, G. (Giulio), Gersh, B.J. (Bernard), Bartúnek, J. (Jozef), Duckers, E. (Eric), Ferdinandy, P. (Péter), Losordo, D.W. (Douglas W.), Čanchez, P.L. (Pedro L.), Sherman, W. (Warren), Wojakowski, W. (Wojtek), Zeiher, A.M. (Andreas), Roncalli, J. (Jérôme), Mathur, A. (Anthony), Crea, F. (Filippo), D'Amario, D. (Domenico), Povsic, T.J. (Thomas J.), Traverse, J.H. (Jay), and Ylä-Herttuala, S. (Seppo)

Published
2017
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20. Late Diastolic Strain Index Is a Marker of Right Ventricular Fibrosis Content in Precapillary Pulmonary Hypertension

Author

Boulate, D., primary, Haddad, F., additional, Noly, P., additional, Kuznetsova, T., additional, Giraldeau, G., additional, Dorfmuller, P., additional, Kobayashi, Y., additional, Decante, B., additional, Wu, J.C., additional, Liang, D., additional, Schnittger, I., additional, Humbert, M., additional, Fadel, E., additional, and Mercier, O., additional

Published
2015
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21. Normalized Right Isovolumic Relaxation Time and Post-Stress Myocardial Deformation Imaging Reveal Early Signs of Precapillary Pulmonary Hypertension: Insights From a Large Animal Model of Chronic Pressure Overload and Clinical Validation

Author

Boulate, D., primary, Giraldeau, G., additional, Guihaire, J., additional, Decante, B., additional, Skhiri, M., additional, Schnittger, I., additional, Humbert, M., additional, Wu, J.C., additional, Zamanian, R.T., additional, Fadel, E., additional, Mercier, O., additional, and Haddad, F., additional

Published
2015
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26. Immunogenicity and tumorigenicity of pluripotent stem cells

Author

Kooreman, N.G., Hamming, J.F., Quax, P.H.A., Wu, J.C., Mummery, C.L., Verhaar, M.C., Schrepfer, S., Goumans, M.J.T.H., Vahrmeijer, A.L., and Leiden University

Subjects
stem cells, regenerative medicine, cell therapy, cancer vaccine, gene therapy
Abstract

This dissertation gives a detailed description of the immunogenic and tumorigenic properties of pluripotent stem cells, such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). More specifically, a clinically relevant insight is given into the immune response towards pluripotent stem cells and how this immune reaction could be limited for stem cell therapies. In addition, gene and stem cell therapies are described for the treatment of peripheral artery disease and abdominal aortic aneurysms.In the final chapter, the immunogenic and tumorigenic properties of iPSCs are used as an immunotherapy against various types of cancer.

Published
2020

27. Basic research in cardiovascular disease : from stem cells to immunomodulation

Author

Lijkwan, M.A., Hamming, J.F., Quax, P.H.A., Wu, J.C., and Leiden University

Subjects
Immunomodulation, Ischemic heart disease, Peripheral arterial disease, Stem cells
Abstract

This thesis addresses basic questions on cellular based and non-cellular (molecular) based therapeutic angiogenesis and provides valuable information on the resident vascular stem cell niche. As the world population ages, the incidence of cardiovascular diseases and its morbidity and mortality are expected to rise. Traditional treatment of cardiovascular diseases such as minimizing risk factors (e.g. smoking cessation), exercise in case of PAD to promote collateral blood flow, pharmaceutical vasodilatation, and surgical revascularization, clearly does not suffice. Therefore, basic cardiovascular research from stem cells to immunomodulation is of utmost importance, eventually leading to further mechanistic insights and a broader range of therapeutic options for patients with cardiovascular disease.

Published
2015

28. (948) - Normalized Right Isovolumic Relaxation Time and Post-Stress Myocardial Deformation Imaging Reveal Early Signs of Precapillary Pulmonary Hypertension: Insights From a Large Animal Model of Chronic Pressure Overload and Clinical Validation.

Author

Boulate, D., Giraldeau, G., Guihaire, J., Decante, B., Skhiri, M., Schnittger, I., Humbert, M., Wu, J.C., Zamanian, R.T., Fadel, E., Mercier, O., and Haddad, F.

Subjects
*RELAXATION therapy, *CARDIOMYOPATHIES, *PULMONARY hypertension diagnosis, *SYSTOLIC blood pressure, *RIGHT heart ventricle, *ARTERIAL occlusions, *CARDIAC imaging, *DIAGNOSIS, *PHYSIOLOGY
Published
2015
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