{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/108204"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/108204","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"DNA/RNA-targeted therapeutic approaches for myotonic dystrophy type 1","abstract":"The student, JuYeon Lee, accepted the attached license on 2018-04-18 at 14:13.","abstract_html":"The student, JuYeon Lee, accepted the attached license on 2018-04-18 at 14:13.","abstract_has_math":false,"creators":["Lee, JuYeon"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["Zimmerman, Steven C","Kalsotra, Auinash","van der Donk, Wilfred","Huang, Raven H"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-08-27T00:46:42Z","date_published":"2020-08-27T00:46:42Z","updated_at":"2026-07-22T22:24:48Z","subjects":["DNA/RNA-targeted therapeutics, myotonic dystrophy type 1, DM1, small molecules targeting DNA/RNA"],"languages":["en"],"rights":["Copyright 2018 JuYeon Lee"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/108204","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Zimmerman, Steven C","Kalsotra, Auinash","van der Donk, Wilfred","Huang, Raven H"]},{"key":"dc:creator","label":"Author","values":["Lee, JuYeon"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2020-08-27T00:46:42Z","2022-08-27T00:51:40Z","2018-04-18","2018-05"]},{"key":"dc:type","label":"Dc Type","values":["text","Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["DNA/RNA-targeted therapeutics, myotonic dystrophy type 1, DM1, small molecules targeting DNA/RNA"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2018 JuYeon Lee"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/108204"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The student, JuYeon Lee, accepted the attached license on 2018-04-18 at 14:13.","The student, JuYeon Lee, submitted this Dissertation for approval on 2018-04-18 at 14:14.","This Dissertation was approved for publication on 2018-04-18 at 15:13.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12356 on 2020-08-25 at 17:37:59","Made available in DSpace on 2020-08-27T00:46:42Z (GMT). No. of bitstreams: 2 LEE-DISSERTATION-2018.pdf: 13268655 bytes, checksum: a2407862ceeae0ff271e61f219f50cf6 (MD5) LICENSE.txt: 4207 bytes, checksum: 583809c6b57d0e1559e8655b2c1782ab (MD5) Previous issue date: 2018-04-18","New discoveries showing the key role of RNAs in diseases such as cancer and neurodegenerative disorders have led to a paradigm shift in drug discovery. At the same time, transcriptome analyses combined with the structural information provided by X-ray crystallography and NMR spectroscopy have further accelerated progress in the field of RNA-targeted therapeutics. Myotonic dystrophy type 1 (DM1) is an excellent disease for developing RNA-targeted therapeutics because the pathogenesis involves a toxic RNA gain-of-function. DM1 is an incurable multisystemic and neurodegenerative disease that originates in an aberrantly expanded CTG trinucleotide repeat in the 3’-untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Healthy individuals have 5-37 CTG repeats, whereas DM1 patients have expanded repeats ranging from 50 to > 2000 repeats. The repeat length directly correlates with the age of onset and severity of the disease. The corresponding expanded transcript, r(CUG)exp, causes toxicity through multiple pathways including muscleblined-like protein 1 (MBNL1) sequestration, repeat-associated non-ATG (RAN) translation, and reduction of myocyte enhancer factor 2 (Mef2). Chapter 1 reviews the background of DM1 including the pathogenesis and therapeutic approaches that target both the DM1 RNA and DNA. The regular and repetitive structure of r(CUG)exp provides a good target to develop finely tuned multivalent ligands. The rationally designed multivalent ligand and its biological activities will be discussed in Chapter 2. The multivalent ligand contains key features of cell penetrating peptide mimics, allowing carrier-free entry to cells and their nucleus. The ligand regulated r(CUG)exp both at the transcriptional and post-transcriptional level, recovering DM1 molecular features in DM1 cells and in a DM1 liver mouse model. Although the therapeutic strategies regulating r(CUG)exp can recover DM1 symptoms to some extent, the origin of the disease in DNA is not addressed by this approach. Furthermore, d(CTG)exp progressively expands throughout the patient’s lifetime as well as across generations. Chapter 3 discusses the development of a small molecule to modify the repeat instability. This ligand was rationally designed to recognize and alkylate the characteristic structure at d(CTG)exp. By creating a covalent adduct with d(CTG)exp, the ligand functioned as a transcription inhibitor as well as a dCTG repeat modulator. The biological activities in DM1 model cells and DM1 patient cells will be discussed.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2020-05-01","Embargo set by: Seth Robbins for item 115817 Lift date: 2022-08-27T00:46:59Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 115817 Lift date: 2022-08-27T00:50:22Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 115817 Lift date: 2022-08-27T00:51:40Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Author requested closed access (OA after 2yrs) in Vireo ETD system","Limited"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["DNA/RNA-targeted therapeutic approaches for myotonic dystrophy type 1"]}]}],"canonical_facts":{"dc:contributor":["Zimmerman, Steven C","Kalsotra, Auinash","van der Donk, Wilfred","Huang, Raven H"],"dc:creator":["Lee, JuYeon"],"dc:date":["2020-08-27T00:46:42Z","2022-08-27T00:51:40Z","2018-04-18","2018-05"],"dc:description":["The student, JuYeon Lee, accepted the attached license on 2018-04-18 at 14:13.","The student, JuYeon Lee, submitted this Dissertation for approval on 2018-04-18 at 14:14.","This Dissertation was approved for publication on 2018-04-18 at 15:13.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12356 on 2020-08-25 at 17:37:59","Made available in DSpace on 2020-08-27T00:46:42Z (GMT). No. of bitstreams: 2 LEE-DISSERTATION-2018.pdf: 13268655 bytes, checksum: a2407862ceeae0ff271e61f219f50cf6 (MD5) LICENSE.txt: 4207 bytes, checksum: 583809c6b57d0e1559e8655b2c1782ab (MD5) Previous issue date: 2018-04-18","New discoveries showing the key role of RNAs in diseases such as cancer and neurodegenerative disorders have led to a paradigm shift in drug discovery. At the same time, transcriptome analyses combined with the structural information provided by X-ray crystallography and NMR spectroscopy have further accelerated progress in the field of RNA-targeted therapeutics. Myotonic dystrophy type 1 (DM1) is an excellent disease for developing RNA-targeted therapeutics because the pathogenesis involves a toxic RNA gain-of-function. DM1 is an incurable multisystemic and neurodegenerative disease that originates in an aberrantly expanded CTG trinucleotide repeat in the 3’-untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. Healthy individuals have 5-37 CTG repeats, whereas DM1 patients have expanded repeats ranging from 50 to > 2000 repeats. The repeat length directly correlates with the age of onset and severity of the disease. The corresponding expanded transcript, r(CUG)exp, causes toxicity through multiple pathways including muscleblined-like protein 1 (MBNL1) sequestration, repeat-associated non-ATG (RAN) translation, and reduction of myocyte enhancer factor 2 (Mef2). Chapter 1 reviews the background of DM1 including the pathogenesis and therapeutic approaches that target both the DM1 RNA and DNA. The regular and repetitive structure of r(CUG)exp provides a good target to develop finely tuned multivalent ligands. The rationally designed multivalent ligand and its biological activities will be discussed in Chapter 2. The multivalent ligand contains key features of cell penetrating peptide mimics, allowing carrier-free entry to cells and their nucleus. The ligand regulated r(CUG)exp both at the transcriptional and post-transcriptional level, recovering DM1 molecular features in DM1 cells and in a DM1 liver mouse model. Although the therapeutic strategies regulating r(CUG)exp can recover DM1 symptoms to some extent, the origin of the disease in DNA is not addressed by this approach. Furthermore, d(CTG)exp progressively expands throughout the patient’s lifetime as well as across generations. Chapter 3 discusses the development of a small molecule to modify the repeat instability. This ligand was rationally designed to recognize and alkylate the characteristic structure at d(CTG)exp. By creating a covalent adduct with d(CTG)exp, the ligand functioned as a transcription inhibitor as well as a dCTG repeat modulator. The biological activities in DM1 model cells and DM1 patient cells will be discussed.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2020-05-01","Embargo set by: Seth Robbins for item 115817 Lift date: 2022-08-27T00:46:59Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 115817 Lift date: 2022-08-27T00:50:22Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Embargo set by: Seth Robbins for item 115817 Lift date: 2022-08-27T00:51:40Z Reason: Author requested closed access (OA after 2yrs) in Vireo ETD system","Author requested closed access (OA after 2yrs) in Vireo ETD system","Limited"],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/2142/108204"],"dc:language":["en"],"dc:rights":["Copyright 2018 JuYeon Lee"],"dc:subject":["DNA/RNA-targeted therapeutics, myotonic dystrophy type 1, DM1, small molecules targeting DNA/RNA"],"dc:title":["DNA/RNA-targeted therapeutic approaches for myotonic dystrophy type 1"],"dc:type":["text","Thesis"],"thesis:degree_discipline":["Chemistry"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:24:48Z"}