INTEGRATED BIOLOGY of EXTRACELLULAR MATRIX, CELLS and PROTEASES in MORPHOGENESIS and HUMAN DISORDERS
Extracellular matrix (ECM)is the inanimate material that surrounds cells and provides a scaffold for tissue and organ architecture. Although inanimate, it is not static and undergoes constant remodeling by proteases. We undertake fundamental research on ECM and proteases and apply it to a variety of diseases. One class of proteases, the ADAMTS proteases, is a major focus of this laboratory, which studies their intrinsic properties, biological mechanisms and roles in human disease. We investigate how their mutations cause birth defects affecting the neural tube, eyes, palate, limbs, heart and blood vessels. Our research is relevant to inherited human connective tissue disorders such as Marfan syndrome and the acromelic dysplasias. We investigate acquired human disorders such as aortic aneurysms, arthritis, cancer, cardiac failure and glaucoma. The technologies employed in the laboratory include biochemistry, cell biology, and genetics. The laboratory makes extensive use of proteomics to identify protease substrates and define the proteolytic landscape of diseased human tissues.
Brief biography: Suneel Apte graduated from medical school at Bombay University. He interrupted his clinical training as an orthopaedic surgeon to obtain the D. Phil degree at the University of Oxford (Mentor: John Kenwright), where he was a Rhodes Scholar. He subsequently trained as a post-doctoral fellow with Bjorn Olsen at Harvard Medical School.
Research support:The laboratory has received support from several NIH institutes, including NIAMS, NEI, NICHD and the NIH-NHLBI Program of Excellence in Glycosciences, the Marfan Foundation, Arthritis Foundation and Sabrina's Foundation. Our current research is supported by the NIH-NHLBI, The Marfan Foundation and the Allen Distinguished Investigator Program, through support made by The Paul G. Allen Frontiers Group and the American Heart Association
Research articles (2019):
Wang LW, Nandadasa S, Annis DS, Dubail J, Mosher DF, Willard BB,Apte SS. A disintegrin-like and metalloproteinase domain with thrombospondin type 1 motif 9 (ADAMTS9) regulates fibronectin fibrillogenesis and turnover. J Biol Chem, 2019,294:9924-9936. doi: 10.1074/jbc.RA118.006479
Nandadasa, S, Kraft, CM, O’Donnell, A, Wang, LW, O’Donnell, A, Patel, R, Gee HY,Grobe, K, Cox, TC, Hildebrandt F and Apte, SS. Secreted metalloproteases ADAMTS9 and ADAMTS20 have a non-canonical role in ciliary vesicle growth during ciliogenesis.Nature Communications,(2019) 10:953 | https://doi.org/10.1038/s41467-019-08520-7
Choi YJ, Halbritter J, Braun DA, Schueler M, Schapiro D, Rim JH, Nandadasa S, Choi WI, Widmeier E, Shril S, Körber F, Sethi SK, Lifton RP, Beck BB, Apte SS, Gee HY,Hildebrandt F. Mutations of ADAMTS9 Cause Nephronophthisis-Related Ciliopathy.Am J Hum Genet. 2019 104:45-54. doi: 10.1016/j.ajhg.2018.11.003.
Wang LW, Kutz WE, Mead TJ, Beene LC, Singh S, Jenkins MW, Reinhardt DP,Apte SS.Adamts10inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage.Matrix Biol.2019, 77:117-128. pii: S0945-053X(18)30253-1. doi: 10.1016/j.matbio.2018.09.004.
Jensen LD, Hot B, Ramsköld D, Germano RFV, Yokota C, Giatrellis S, Lauschke VM, Hubmacher D, Li MX, Hupe M, Arnold TD, Sandberg R, Frisén J, Trusohamn M, Martowicz A, Wisniewska-Kruk J, Nyqvist D, Adams RH,Apte SS, Vanhollebeke B, Stenman JM, Kele J.Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling.Arterioscler Thromb Vasc Biol. 2019 39:1432-1447. doi: 10.1161/ATVBAHA.119.312388.
Graae AS, Grarup N, Ribel-Madsen R, Lystbæk SH, Boesgaard T, Staiger H, Fritsche A, Wellner N, Sulek K, Kjolby M, Backe MB, Chubanava S, Prats C, Serup AK, Birk JB, Dubail J, Gillberg L, Vienberg SG, Nykjær A, Kiens B, Wojtaszewski JFP, Larsen S, Apte SS, Häring HU, Vaag A, Zethelius B, Pedersen O, Treebak JT, Hansen T, Holst B.ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through ExtracellularMatrix Alterations.Diabetes. 68(3):502-514.doi: 10.2337/db18-0418. [Epub ahead of print]
Laboratory activities 2019:
Chris Koch, a PhD candidate in Cleveland State University's Department of Chemistry, successfully defended his PhD thesis in April 2019. He will take up a fellowship in Clinical Chemistry at Yale University later this year.
Sumeda Nandadasa's recent publications on biogenesis of the primary cilium and related genetic defects were highlighted in the LRI newsletter:https://www.lerner.ccf.org/news/details/?The+Unexpected+Role+of+Secreted+Proteases+in+Birth+Defects&f347b7699ccf143f7f6a1e0be20482ba8056cb07&23a16c844211d6cb3badb5cd6bbec799057d3323
Sumit Bhutada presented his work at the 2019 ASMB Workshop on Fibroblasts, Charlottesville, VA.
Daniel Martin andSumit Bhutada presented posters at the 2019 ASMS Conference, Atlanta, GA.
Research articles (2018):
Mead TJ, Du Y, Nelson CM, Gueye N-A, Drazba J, Dancevic CM, Vankemmelbeke M, Buttle DJ, Apte SS.ADAMTS9-Regulated Pericellular Matrix Dynamics Governs Focal Adhesion-Dependent Smooth Muscle Differentiation.Cell Reports.2018, 23; 2, 485-498.
MeadTJ, McCulloch DR, Ho JC, Du Y, Adams SM, Birk DE,ApteSS.The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification.JCI Insight.2018 April5;3(7). pii: 92941. doi: 10.1172/jci.insight.92941
Cikach FS, Koch CD, Mead TJ, Galatioto J, Willard BB, Emerton KB, Eagleton MJ, Blackstone EH, Ramirez F, Roselli EE,Apte SS.Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection.JCI Insight.2018 Mar 8;3(5). pii: 97167. doi: 10.1172/jci.insight.97167.
Prins, B. , Mead, T.J. (joint first authors) et al.Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.Genome Biol 2018, 19:87.https://doi.org/10.1186/s13059-018-1457-6
Schnellmann R, Sack R, Hess D, Annis DS,MosherDF,ApteSS, Chiquet-Ehrismann R.A selective extracellular matrix proteomics approach identifies fibronectin proteolysis by ADAMTS16 and its impact on spheroid morphogenesis.Mol Cell Proteomics.2018 Apr 18. pii: mcp.RA118.000676. doi: 10.1074/mcp.RA118.000676. [Epub ahead of print]
Aviram R, Zaffryar-Eilot S, Hubmacher D, Grunwald H, Mäki JM, Myllyharju J,Apte SS, Hasson P.Interactions between lysyl oxidases and ADAMTS proteins suggest a novel crosstalk between two extracellular matrix families. Matrix Biol. 2018 May 11. pii: S0945-053X(17)30448-1. doi: 10.1016/j.matbio.2018.05.003. [Epub ahead of print]
Please click on the publications tab at the top of this page for earlier publications or visit Dr. Apte's profile on Google Scholar and at http://www.ncbi.nlm.nih.gov/pubmed/
Laboratory activities 2018:
Sumeda Nandadasa and Tim Mead received awards for their presentations at the 2018 American Society for Matrix Biology Conference, Las Vegas, October 14-17, 2018. Chris Koch and Debbie Hoelting presented posters at this conference.
Timothy Mead was selected to attend the 2018 Neonatal Cardiopulmonary Biology Young Investigators Forum in Chicago IL. Sept. 6-9th2018, where he was awarded a 2018 Excellence in Research Grant.
Sumit Bhutada and Daniel Martin attended a workshop on the Trans-Proteomic Pipeline in Florida in September
Chris Koch attended the 2018 American Association for Clinical Chemistry National Meeting in Chicago, IL. He recieved a travel grant and was selected to participate in the student oral presentation competition. For his talk “Assay Development and Evaluation of Serum Aggrecan and Versican as Novel Biomarkers for Thoracic Aortic Aneurysm and Dissection” he was awarded first place.
Sumeda Nandadasa's abstract was selected for a podium presentation at the Gordon Research Conference on Protein Processing, Trafficking and Secretion in New Hampshire, July 15-20, 2018
Chris Koch presented his work at the Gordon Research Conference on Proteoglycans in New Hampshire,July 8-13 2018.
A sampling of research publications from 2017 and earlier:
1. Hubmacher D, Schneider M, Berardinelli S, Takeuchi H, Willard B, Reinhardt DH, Haltiwanger R, and Apte SS. Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease. Scientific Reports, 2017;7:41871. doi: 10.1038/srep41871.
2. Dubail, J, Vasudevan, D, Wang, LW, Earp, SE, Jenkins, MW, Haltiwanger, RS, and Apte SS. Impaired ADAMTS9 secretion: A potential mechanism for eye defects in Peters Plus Syndrome. Scientific Reports. 2016. 6:33974. doi: 10.1038/srep33974.
3. Nandadasa, S., Nelson, C.M., Apte, SS. ADAMTS9-Mediated Extracellular Matrix Dynamics Regulates Umbilical Cord Vascular Smooth Muscle Differentiation and Rotation. Cell Reports 11:1519-28, 2015
4. Enomoto, H., Nelson, C., Somerville, R.P.T., Mielke, K., Dixon, L., Powell, K., Apte, S.S. Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation. Development, 2010, 37:4029-38.
5. McCulloch, D.R., Nelson, C.M., Dixon, L.J., Silver D.L., Wylie, J.D., Lindner, V., Sasaki, T., Cooley, M.A., Argraves, W.S. and Apte, S.S. ADAMTS metalloproteases generate active versican fragments that regulate interdigital web regression. Developmental Cell 2009, 17:687-98. PMCID:PMC2780442.
Recent literature reviews, technical reports and commentaries:
2. Apte, SS. Anti-ADAMTS5 monoclonal antibodies: implications for aggrecanase inhibition in osteoarthritis. Biochem J. 2016 Jan 1;473(1):e1-e4
3. Dubail J, Apte SS. Insights on ADAMTS proteases and ADAMTS-like proteins from mammalian genetics.Matrix Biol. 44-46:24-37 2015
4. Foulcer SJ, Day AJ, Apte SS. Isolation and purification of versican and analysis of versican proteolysis. Methods Mol Biol. 1229:587-604, 2015
5. Nandadasa S, Foulcer S, Apte SS. The multiple, complex roles of versican and its proteolytic turnover by ADAMTS proteases during embryogenesis. Matrix Biol. 2014, 35:34-41, 2014.
1. Apte, SS. Chapter 259. Connective Tissue Structure and Function. ed. Goldman L, and Shafer, A.I., Goldman-Cecil Textbook of Medicine, Twenty-Fifth Edition, Elsevier, New York, 2016, ISBN 9781455750177
2. Apte SS. ADAMTS proteases: Mediators of physiological and pathogenic extracellular proteolysis, in Bradshaw, R., and Stahl, P, eds, Encyclopedia of Cell Biology, Elsevier, New York, 2015, ISBN 9780123944474
3. Apte, SS. Chapter 2. Overview of the ADAMTS superfamily, in Rodgers, G., ed, ADAMTS13: Biology and Disease, Springer, New York, 2015, ISBN 9783319087160
4. Traboulsi I, and Apte SS. Chapter 43. Ectopia Lentis and Associated Systemic Disease, in Traboulsi, I., ed, Genetic Diseases of the Eye, Second Edition, Oxford University Press, USA, 2012, ISBN 9780195326147
Additional publications from our laboratory are obtainable from Dr. Apte's profile on Google Scholar and at http://www.ncbi.nlm.nih.gov/pubmed/
|US Patent||Patent Title||Issue Date||First-Named Inventor|
|6,391,610||Nucleic Acids Encoding Zinc Metalloproteases||5/21/2002||Suneel S. Apte Ph.D|
A group of Cleveland Clinic researchers have identified how the proteases ADAMTS9 and ADAMTS20 contribute to embryonic development and how defects in these enzymes lead to serious birth defects.
An international team of researchers, including scientists from Lerner Research Institute, has uncovered new loci (chromosomal regions) associated with heart function and development.
Rates of fetal and maternal morbidity and mortality in the United States are on the rise. A new Cleveland Clinic study shows how abnormal accumulation of extracellular matrix (ECM) prevents smooth muscle cells (SMCs) in the uterus from properly contracting, which can cause prolonged or arrested delivery and lead to poor health outcomes.