{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/101343"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/101343","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Structural determinants of cardiac light chain amyloidosis","abstract":"Light chain amyloidosis (AL) is an acute systemic amyloid disease in which the overexpression and misfolding of immunoglobulin light chains leads to the formation of insoluble fibrils at critical organs in the body. The typical prognosis for AL patients is extremely severe—usually less than three years of diagnosis—but in the case of cardiac involvement, this is reduced to under a year. As a result of the complex and diverse nature of the disease, our understanding of how it onsets and imparts its devastating effects remains elusive, consequently delaying progress on the identification of robust diagnostic and therapeutic strategies. To address this deficiency, we investigate the structural and dynamical properties of the fibrils involved in a severe case of cardiac AL disease, formed from the light-chain variable domain (VL) patient-derived protein, AL-09. We performed these studies through the use of solid-state nuclear magnetic resonance (SSNMR) spectroscopy, which have revealed new insights on specific features of the fibril species. First, we report our findings on the 13C and 15N chemical shift assignments and sequence involvement of AL-09 VL fibrils, followed by subsequent investigations on the predominant secondary structure and relative dynamics across the protein sequence. In addition, we present a comparison of AL-09 VL fibrils (prepared in vitro) with ex vivo amyloid deposits of another AL protein fibril (HIG) obtained from human spleen tissue using 1D 13C SSNMR analysis. Next, we describe the development and implementation of 4D 13C-detected SSNMR experiments that combine non-uniform sampling with band-selective J-decoupling pulses to enable the resolution of previously unassignable resonances while maintaining high sensitivity. Last, we introduce an improved program and strategy for the computationally-aided assignment of protein chemical shifts that incorporates peak intensity and frequency overlap information as an additional scoring function in the multi-objective search for optimal assignment solutions.","abstract_html":"Light chain amyloidosis (AL) is an acute systemic amyloid disease in which the overexpression and misfolding of immunoglobulin light chains leads to the formation of insoluble fibrils at critical organs in the body. The typical prognosis for AL patients is extremely severe—usually less than three years of diagnosis—but in the case of cardiac involvement, this is reduced to under a year. As a result of the complex and diverse nature of the disease, our understanding of how it onsets and imparts its devastating effects remains elusive, consequently delaying progress on the identification of robust diagnostic and therapeutic strategies. To address this deficiency, we investigate the structural and dynamical properties of the fibrils involved in a severe case of cardiac AL disease, formed from the light-chain variable domain (VL) patient-derived protein, AL-09. We performed these studies through the use of solid-state nuclear magnetic resonance (SSNMR) spectroscopy, which have revealed new insights on specific features of the fibril species. First, we report our findings on the 13C and 15N chemical shift assignments and sequence involvement of AL-09 VL fibrils, followed by subsequent investigations on the predominant secondary structure and relative dynamics across the protein sequence. In addition, we present a comparison of AL-09 VL fibrils (prepared in vitro) with ex vivo amyloid deposits of another AL protein fibril (HIG) obtained from human spleen tissue using 1D 13C SSNMR analysis. Next, we describe the development and implementation of 4D 13C-detected SSNMR experiments that combine non-uniform sampling with band-selective J-decoupling pulses to enable the resolution of previously unassignable resonances while maintaining high sensitivity. Last, we introduce an improved program and strategy for the computationally-aided assignment of protein chemical shifts that incorporates peak intensity and frequency overlap information as an additional scoring function in the multi-objective search for optimal assignment solutions.","abstract_has_math":false,"creators":["Piehl, Dennis W."],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Biochemistry","degree_department":null,"school":null,"contributors":["Rienstra, Chad M.","Gennis, Robert B.","Nair, Satish K.","Gruebele, Martin H.W."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2018,"date_issued":"2018-09-04T20:47:21Z","date_published":"2018-09-04T20:47:21Z","updated_at":"2026-07-22T22:24:38Z","subjects":["solid-state NMR, light chain amyloidosis"],"languages":["en"],"rights":["Copyright 2018 Dennis Piehl"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/101343","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Rienstra, Chad M.","Gennis, Robert B.","Nair, Satish K.","Gruebele, Martin H.W."]},{"key":"dc:creator","label":"Author","values":["Piehl, Dennis W."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2018-09-04T20:47:21Z","2020-09-05T09:15:13Z","2018-04-20","2018-05"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biochemistry"]},{"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":["solid-state NMR, light chain amyloidosis"]}]},{"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 Dennis Piehl"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/101343"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Light chain amyloidosis (AL) is an acute systemic amyloid disease in which the overexpression and misfolding of immunoglobulin light chains leads to the formation of insoluble fibrils at critical organs in the body. The typical prognosis for AL patients is extremely severe—usually less than three years of diagnosis—but in the case of cardiac involvement, this is reduced to under a year. As a result of the complex and diverse nature of the disease, our understanding of how it onsets and imparts its devastating effects remains elusive, consequently delaying progress on the identification of robust diagnostic and therapeutic strategies. To address this deficiency, we investigate the structural and dynamical properties of the fibrils involved in a severe case of cardiac AL disease, formed from the light-chain variable domain (VL) patient-derived protein, AL-09. We performed these studies through the use of solid-state nuclear magnetic resonance (SSNMR) spectroscopy, which have revealed new insights on specific features of the fibril species. First, we report our findings on the 13C and 15N chemical shift assignments and sequence involvement of AL-09 VL fibrils, followed by subsequent investigations on the predominant secondary structure and relative dynamics across the protein sequence. In addition, we present a comparison of AL-09 VL fibrils (prepared in vitro) with ex vivo amyloid deposits of another AL protein fibril (HIG) obtained from human spleen tissue using 1D 13C SSNMR analysis. Next, we describe the development and implementation of 4D 13C-detected SSNMR experiments that combine non-uniform sampling with band-selective J-decoupling pulses to enable the resolution of previously unassignable resonances while maintaining high sensitivity. Last, we introduce an improved program and strategy for the computationally-aided assignment of protein chemical shifts that incorporates peak intensity and frequency overlap information as an additional scoring function in the multi-objective search for optimal assignment solutions.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2020-05-01","The student, Dennis Piehl, accepted the attached license on 2018-04-18 at 05:51.","The student, Dennis Piehl, submitted this Dissertation for approval on 2018-04-18 at 06:44.","This Dissertation was approved for publication on 2018-04-20 at 09:41.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12332 on 2018-08-31 at 17:29:46","Made available in DSpace on 2018-09-04T20:47:21Z (GMT). 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The typical prognosis for AL patients is extremely severe—usually less than three years of diagnosis—but in the case of cardiac involvement, this is reduced to under a year. As a result of the complex and diverse nature of the disease, our understanding of how it onsets and imparts its devastating effects remains elusive, consequently delaying progress on the identification of robust diagnostic and therapeutic strategies. To address this deficiency, we investigate the structural and dynamical properties of the fibrils involved in a severe case of cardiac AL disease, formed from the light-chain variable domain (VL) patient-derived protein, AL-09. We performed these studies through the use of solid-state nuclear magnetic resonance (SSNMR) spectroscopy, which have revealed new insights on specific features of the fibril species. First, we report our findings on the 13C and 15N chemical shift assignments and sequence involvement of AL-09 VL fibrils, followed by subsequent investigations on the predominant secondary structure and relative dynamics across the protein sequence. In addition, we present a comparison of AL-09 VL fibrils (prepared in vitro) with ex vivo amyloid deposits of another AL protein fibril (HIG) obtained from human spleen tissue using 1D 13C SSNMR analysis. Next, we describe the development and implementation of 4D 13C-detected SSNMR experiments that combine non-uniform sampling with band-selective J-decoupling pulses to enable the resolution of previously unassignable resonances while maintaining high sensitivity. Last, we introduce an improved program and strategy for the computationally-aided assignment of protein chemical shifts that incorporates peak intensity and frequency overlap information as an additional scoring function in the multi-objective search for optimal assignment solutions.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2020-05-01","The student, Dennis Piehl, accepted the attached license on 2018-04-18 at 05:51.","The student, Dennis Piehl, submitted this Dissertation for approval on 2018-04-18 at 06:44.","This Dissertation was approved for publication on 2018-04-20 at 09:41.","DSpace SAF Submission Ingestion Package generated from Vireo submission #12332 on 2018-08-31 at 17:29:46","Made available in DSpace on 2018-09-04T20:47:21Z (GMT). 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