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001 on1056953878;

003 OCoLC;

005 20190207022024.0;

006 m o d ;

007 cr unu||||||||;

008 181015s2018 ncua obm 000 0 eng d;

035 a| (Sirsi) o1056953878;

035 a| (OCoLC)1056953878;

049 a| EREE;

090 a| RC632.A5;

100 1 a| Dasari, Anvesh K. R.,e| author.?| UNAUTHORIZED;

245 10 a| Elucidating the mechanisms of transthyretin aggregation in transthyretin amyloidosis /c| by Anvesh K. R. Dasari.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2018.;

300 a| 122 pages :b| illustrations (chiefly color);

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 5.511 MB2| rda;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph. D.c| East Carolina Universityd| 2018;

500 a| Presented to the faculty of the Interdisciplinary Doctoral Program in Biological Sciences;

500 a| Advisor: Kwang Hun Lim;

500 a| Title from PDF t.p. (viewed February 6, 2019).;

520 3 a| Accumulation of insoluble aggregates (amyloids) is a characteristic feature of many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Aggregation and deposition of Transthyretin (TTR) protein in tissues leads to transthyretin amyloidosis. Aggregation of wild-type (WT) TTR shown to affect the heart, causing senile systemic amyloidosis (SSA), while the two pathogenic mutants (V30M, and L55P) affect the peripheral nervous system. It is important to understand the misfolding/amyloid formation mechanism towards the development of therapeutic strategies. TTR is rich in the [beta]-sheet structure in which eight [beta]-strands are arranged in a [beta]-sandwich consisting of two [beta]-sheets (strands CBEF and DAGH). Previous solution NMR studies have shown that the amyloid precursor state of TTR is also rich in [beta]-sheets. Our solid-state NMR results indicated the presence of intact native-like [beta]-sheets in the amyloid state as well. But, the AB loop region appeared to be perturbed during the aggregation which could expose strand A for intermolecular associations. Solid-state NMR results of the mutant forms (V30M and L55P) also indicated the presence of native-like [beta]-sheets in the amyloid states but, with a distorted DA strand which further exposes strand A for more aggressive intermolecular interactions. We also reported the aggregation mechanism for early aggregates which are shown to be cytotoxic in the amyloid formation pathway. We also discovered that the hexamers of TTR are the building blocks of these early toxic aggregates.;

504 a| Includes bibliographical references.;

650 0 a| Amyloidosis.=| ^A906223;

653 a| Solid-state NMR;

655 7 a| Academic theses.2| lcgft;

700 1 a| Lim, Kwang Hun,e| degree supervisor.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Chemistry.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/6987;

949 o| wjh;

994 a| C0b| ERE;

596 a| 1 4;

998 a| 4931032;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 4931032-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 10/15/2018x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 4931032-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 10/15/2018x| ETDz| HERESOURCE;

Elucidating the mechanisms of transthyretin aggregation in transthyretin amyloidosis / by Anvesh K. R. Dasari.

Author/creator	Dasari, Anvesh K. R. author.
Other author	Lim, Kwang Hun, degree supervisor.
Other author	East Carolina University. Department of Chemistry.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2018.
Description	122 pages : illustrations (chiefly color)
Supplemental Content	Access via ScholarShip
Subjects	Amyloidosis.

Summary	Accumulation of insoluble aggregates (amyloids) is a characteristic feature of many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Aggregation and deposition of Transthyretin (TTR) protein in tissues leads to transthyretin amyloidosis. Aggregation of wild-type (WT) TTR shown to affect the heart, causing senile systemic amyloidosis (SSA), while the two pathogenic mutants (V30M, and L55P) affect the peripheral nervous system. It is important to understand the misfolding/amyloid formation mechanism towards the development of therapeutic strategies. TTR is rich in the [beta]-sheet structure in which eight [beta]-strands are arranged in a [beta]-sandwich consisting of two [beta]-sheets (strands CBEF and DAGH). Previous solution NMR studies have shown that the amyloid precursor state of TTR is also rich in [beta]-sheets. Our solid-state NMR results indicated the presence of intact native-like [beta]-sheets in the amyloid state as well. But, the AB loop region appeared to be perturbed during the aggregation which could expose strand A for intermolecular associations. Solid-state NMR results of the mutant forms (V30M and L55P) also indicated the presence of native-like [beta]-sheets in the amyloid states but, with a distorted DA strand which further exposes strand A for more aggressive intermolecular interactions. We also reported the aggregation mechanism for early aggregates which are shown to be cytotoxic in the amyloid formation pathway. We also discovered that the hexamers of TTR are the building blocks of these early toxic aggregates.
General note	Presented to the faculty of the Interdisciplinary Doctoral Program in Biological Sciences
General note	Advisor: Kwang Hun Lim
General note	Title from PDF t.p. (viewed February 6, 2019).
Dissertation note	Ph. D. East Carolina University 2018
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.
Genre/form	Academic theses.

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