• Refine Query
  • Source
  • Publication year
  • to
  • Language
  • 1
  • 1
  • Tagged with
  • 2
  • 2
  • 2
  • 2
  • 2
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • 1
  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Kinetics of Aβ Peptide Deposition: Toward <i>In Vivo</i> Imaging of Alzheimer’s Disease Amyloid

Marshall, Jeffrey Richard 21 May 2002 (has links)
No description available.
2

Defining cellular and molecular mechanisms of hereditary transthyretin amyloidosis

Giadone, Richard Michael 29 May 2020 (has links)
Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a multi-system protein folding disorder that results from >100 described mutations in the transthyretin (TTR) gene. In the disease, non-natively folded TTR, originally produced by the liver, travels throughout circulation and deposits extracellularly at downstream target organs. The multi-tissue etiology of the disease makes it difficult to study in vitro, while no mouse model accurately recapitulates disease pathology. Therefore, we utilized patient-specific induced pluripotent stem cells (iPSCs) to test the hypothesis that production of and exposure to destabilized TTRs results in distinct cellular and molecular changes. The liver’s contribution to the deposition of TTR at distal tissues is understudied. As a result, in Aim 1 we sought to assess the effects of destabilized TTR production on effector hepatic cells. To this end, we utilized gene editing to generate isogenic, patient iPSCs expressing either mutant or wild-type TTR. Combining this tool with single cell RNAseq, we identified hepatic proteostasis factors, including unfolded protein response (UPR) pathways, whose expression coincided with the production of destabilized TTR. Enhancing endoplasmic reticulum (ER) proteostasis within patient hepatic cells via exogenous activation of adaptive UPR signaling, we demonstrated preferential reduction in the secretion of pathogenic TTR. In turn, we demonstrated that production of disease-associated TTR correlates with expression of proteostasis factors capable of regulating TTR secretion and in turn downstream pathogenesis. ATTR amyloidosis patients exhibit extreme phenotypic variation (e.g. TTR fibril deposits at cardiac tissue and/or peripheral nerves). In Aim 2, we sought to define responses of target cell types to pathologically-diverse TTRs. To accomplish this, we profiled transcriptomic changes resulting from exposure to a variety of destabilized TTRs to determine 1) target cell response to TTR exposure and 2) how this response changes across diverse variants and cell types. In doing so, we found that TTR exposure elicits distinct variant- and cell type-specific transcriptional responses. Herein, we addressed our central hypothesis by profiling destabilized TTR production within hepatic cells and TTR exposure at target cell types. Collectively, these data may result in the discovery of unidentified and potentially druggable pathologically-associated pathways for ATTR amyloidosis and other systemic amyloid diseases.

Page generated in 0.1098 seconds