Uncovering Cell Type-Specific Phenotypes Using a Novel Human In vitro Model of Transthyretin Amyloid Cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA1247885 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33016546_1.fastq.gz | Fastqsanger.gz | |||
| SRR33016546_2.fastq.gz | Fastqsanger.gz | |||
| SRR33016547_1.fastq.gz | Fastqsanger.gz | |||
| SRR33016547_2.fastq.gz | Fastqsanger.gz | |||
| SRR33016548_1.fastq.gz | Fastqsanger.gz |
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Project description:Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the misfolding of transthyretin (TTR), fibrillogenesis, and progressive amyloid fibril deposition in the myocardium, leading to cardiac dysfunction with dismal prognosis. In ATTR-CM, either destabilizing mutations (variant TTR, ATTRv) or ageing-associated processes (wild-type TTR, ATTRwt) lead to the formation of TTR amyloid fibrils. Due to a lack of representative disease models, ATTR-CM disease mechanisms are largely unknown, thereby limiting disease understanding and therapeutic discovery. Methods and Results: Here, we report a novel in vitro ATTR-CM model which uncovers cell type-specific disease phenotypes by exposing the three major human cardiac cell types to TTR fibrils, thereby providing novel insights into the cellular mechanisms of ATTR-CM disease. Human recombinant TTR proteins (WT, V122I, V30M) and respective fibrils were generated and characterized using Thioflavin T, Amytracker, Congo red and dot blot analyses. Seeding human induced pluripotent stem cell-derived-cardiomyocytes (hiPSC-CMs) and endothelial cells (ECs) on TTR fibrils resulted in reduced cell viability. Confocal microscopy revealed extracellular localization of TTR fibrils to hiPSC-CMs, leading to sarcomere disruption, altered calcium handling and disrupted electromechanical coupling, while ECs showed a reduced migration capacity with aberrant cell morphology. hiPSC-fibroblasts (hiPSC-FBs) were largely unaffected by TTR fibrils, presenting normal viability, but showing enhanced localization with TTR fibrils. Our model shows that WT and variant TTR fibrils lead to cell type-specific phenotypes, providing novel insights into the underlying cellular disease mechanisms of ATTR-CM, thereby facilitating the identification of novel therapeutic targets and biomarkers.
2025-06-11 | GSE294021 | GEO
Project description:We have developed a new mouse model of transthyretin (TTR) amyloidosis using transgenic mice expressing the most fibrillogenic variant of TTR (S52P). Following seeding with amyloid fibrils, TTR amyloid is deposited mainly in the heart and tongue. The fibrils contain both full length and truncated (49-127) TTR. The presence of S52P TTR was confirmed by proteomics. Knockout of alpha2-antiplasmin enhanced amyloid deposition.
2021-12-27 | PXD027747 | Pride
Project description:Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g. when the TTR tetramer stabilizer tafamidis was administered to familial amyloid polyneuropathy (FAP) patients early in the disease course. When asked if the findings of the tafamidis registration trial were âsufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefitâ the advisory committee said yes, but the FDA rejected the tetramer stabilization surrogate biomarker required for orphan tafamidis approvalâhence, acceptable biomarkers are badly needed. Herein, we explored whether peripheral blood cell mRNA expression profiles could differentiate symptomatic from asymptomatic V30M FAP patients, and if such a profile would normalize upon tafamidis treatment. We demonstrate that blood cell gene expression patterns reveal sex-independent as well as male and female specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers, that normalize in FAP patients 6 months after tafamidis treatment. Thus these signatures have potential both as an early diagnostic and as a surrogate biomarker for measuring response to treatment in FAP patients. Study Subjects: Tafamidis-treated and untreated V30M FAP patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations had whole blood drawn. RNA was extracted from a total of 309 peripheral blood samples collected in PAXgene tubes (Qiagen). RNA Extraction and Microarray Processing: RNA was extracted with the PAXgene RNA Whole Blood Kit. Each RNA sample (100ng) was amplified and labeled with the Ambion WT Express Kit and hybridized to Affymetrix HuGene 1.1 ST Arrays using the Affymetrix GeneTitan Multi-Channel (MC) platform. Normalized signals were generated using Robust Multichip Average (RMA) in Partek Genomics Suite software version 6.6. Probesets on the DNA microarrays with low expressed signals were determined using a kernel density plot, and signals <Log2 of 6 were excluded from analysis.
2016-08-09 | E-GEOD-67784 | biostudies-arrayexpress
Project description:Early diagnosis of transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease modifying therapies. Early diagnosis is often difficult because the patient exhibits apparent symptoms of polyneuropathy or cardiomyopathy, but has a negative amyloid biopsy. Thus, there is a pressing need for more objective, quantitative diagnostics and biomarkers of TTR-aggregation-associated polyneuropathy and cardiomyopathy. This is especially true in the context of clinical trials demonstrating significant disease modifying effects, e.g. when the TTR tetramer stabilizer tafamidis was administered to familial amyloid polyneuropathy (FAP) patients early in the disease course. When asked if the findings of the tafamidis registration trial were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit” the advisory committee said yes, but the FDA rejected the tetramer stabilization surrogate biomarker required for orphan tafamidis approval–hence, acceptable biomarkers are badly needed. Herein, we explored whether peripheral blood cell mRNA expression profiles could differentiate symptomatic from asymptomatic V30M FAP patients, and if such a profile would normalize upon tafamidis treatment. We demonstrate that blood cell gene expression patterns reveal sex-independent as well as male and female specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers, that normalize in FAP patients 6 months after tafamidis treatment. Thus these signatures have potential both as an early diagnostic and as a surrogate biomarker for measuring response to treatment in FAP patients.
2016-08-09 | GSE67784 | GEO
Project description:Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms
| PRJNA647190 | ENA
Project description:Transthyretin Amyloid Polyneuropathy (ATTR-PN) is characterized by the deposition of amyloidogenic TTR particularly in dorsal root ganglia (DRG) and peripheral nerve axons leading to a sensory axonopathy. Here, we investigated the role of cytoskeleton alterations in peripheral axons from an ATTR-PN mouse model. We employed the knock-in hTTRA97S mouse model for ATTR-PN to examine cellular and molecular changes in peripheral axons. Our approach included proteomic analysis of the sural nerve, live imaging techniques, and pharmacological intervention targeting Rac1. Additionally, we used DNA samples gathered from individuals diagnosed with ATTR-PN, including early-onset and late-onset cases, to uncover genetic variants of cytoskeleton regulators related to distinct disease onsets.
2025-10-10 | PXD054291 | Pride
Project description:Transthyretin variant amyloidosis (ATTRv) is a rare autosomal dominant disease characterized by the accumulation of amyloid in many organs, mostly causing a sensory-motor neuropathy, cardiomyopathy, and dysautonomia. The aim of the study was to report microRNAs (miRNAs) expression profile identified in the blood of ATTRv patients. 10 symptomatic ATTRv patients, 10 asymptomatic carriers of transthyretin variant (TTRv), 10 patients with Charcot-Marie-Tooth (CMT) disease, and 10 healthy controls were studied. Human Schwann cells cultures were used to study the regulatory effects of miR-150-5p on the expression of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF). ATTRv patients had 33 miRNAs up-regulated and 48 down-regulated versus healthy controls; 9 miRNAs were up-regulated and 30 down-regulated versus CMT patients; 19 miRNAs were up-regulated and 38 down-regulated versus asymptomatic TTRv carriers. Twelve out of the 19 upregulated miRNAs had a fold increase higher than 100. The validation experiment indicated miR-150-5p as a valuable biomarker to differentiate ATTRv patients from asymptomatic TTRv carriers (AUC: 0.9728; p<0.0001). Schwann cells culture model demonstrated that miR-150-5p is a powerful negative regulator of CREB, BDNF and NGF genes. Identification of deregulated miRNAs can help in understanding the complex pathomechamism underlying the development of ATTRv and related multisystemic pathology. Further investigations are needed on the role of circulating miR-150-5p to predict the shift of TTRv carriers from an asymptomatic status to symptoms appearance.
2020-05-31 | GSE149665 | GEO
Project description:Transthyretin amyloid cardiomyopathy (ATTR-CM) continues to be an easily overlooked, life-threatening, yet treatable cause of heart failure. Furthermore, its elusive diagnosis leads to late or misdiagnosis. As therapeutic advancements such as tafamidis usher in a promising new era in the management of ATTR-CM, the need for disease awareness and efficient diagnostic evaluation is crucial. With newer inexpensive imaging modalities and techniques, such as longitudinal strain imaging, T1 mapping on cardiac magnetic resonance imaging, and cardiac scintigraphy, the diagnosis of ATTR-CM no longer requires invasive evaluation with tissue biopsy. Here, the authors review current diagnostic tools to help clinicians diagnose ATTR-CM.
| S-EPMC7237598 | biostudies-literature
Project description:The systemic amyloidoses are diverse disorders in which misfolded proteins are secreted by effector organs and deposited as proteotoxic aggregates at downstream tissues. Although well-described clinically, the contribution of synthesizing organs to amyloid disease pathogenesis is unknown. Here, we utilize hereditary transthyretin amyloidosis (ATTR amyloidosis) induced pluripotent stem cells (iPSCs) to define the contribution of HLCs to the proteotoxicity of secreted TTR. To this end, we generated isogenic, patient-specific iPSCs expressing either amyloidogenic or wild-type TTR. We subsequently differentiated these lines into HLCs and performed single cell RNA sequencing (scRNAseq) via the Fluidigm C1 platform in an effort to identify a destabilized TTR-derived disease signature. Upon doing so, we identified a number of hepatic proteostasis factors (e.g. the unfolded protein response, UPR, as well as known and novel chaperone genes) whose expression correlates with the production destabilized TTR production.
2020-07-01 | GSE153541 | GEO
Project description:The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure, peripheral edema, and several other non-cardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator. DNA was extracted from whole blood of Yale-Penn participants using the EZ-96 DNA methylation kit (Zymo Research, CA, USA). DNA methylation was assayed using the Illumina Infinium MethylationEPIC chip quantifying >850,000 CpG sites and imaged on the Illumina iScan system at YCGA. The methylation intensity data (*.idat files) was exported for analysis using the manufacturer's recommended protocol using the GenomeStudio methylation module.
2020-12-31 | GSE154683 | GEO