Richard Giadone

Harvard University | Harvard · Department of Stem Cell and Regenerative Biology

Introduction: Patients with advanced cardiac AL have high early mortality despite receiving effective plasma cell-directed therapies. Cardiac dysfunction is caused by direct myocardial toxicity from amyloidogenic light chains (LCs) and architectural distortion from amyloid fibril deposition. Diagnosis before significant fibril-induced cardiac dysfu...

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex age-related human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities...

RNA sequencing (RNA-seq) is a powerful method of transcriptional analysis that allows for the sequence identification and quantification of cellular transcripts. RNA-seq can be used for differential gene expression (DGE) analysis, gene fusion detection, allele-specific expression, isoform and splice variant quantification, and identification of nov...

Background: In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive. Methods: In an effort to define early events of TT...

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell...

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME pla...

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME is expressed by both mouse and human neurons. GSDME play...

In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive. In an effort to define early events of TTR-associated stress, we...

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell...

Neutrophils mediate critical innate immune responses by migrating to sites of infection or inflammation, phagocytosing microorganisms, and releasing an arsenal of antimicrobial agents, including reactive oxygen species. These functions are shared by other innate immune cell types, but an interesting feature of neutrophils is their hallmark lobulate...

The systemic amyloidoses represent a devastating class of multisystem protein folding disorders whose etiologies involve complex interactions between multiple tissue types (e.g., aberrant protein producing effector and downstream damaged target organs). Problematically, this hallmark multiorgan involvement presents unique challenges for developing...

The protocols herein outline the use of qRT-PCR to detect the presence of SARS-CoV-2 genomic RNA in patient samples. In order to cope with potential fluctuations in supply chain and testing demands and to enable expedient adaptation of reagents and assays on hand, we include details for three parallel methodologies (one- and two-step singleplex and...

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...

Background: Significant delays in the rapid development and distribution of diagnostic testing for SARS-CoV-2 (COVID-19) infection have prevented adequate public health management of the disease, impacting the timely mapping of viral spread and the conservation of personal protective equipment. Furthermore, vulnerable populations, such as those se...

Hereditary transthyretin amyloidosis (ATTR amyloidosis) is an autosomal dominant protein-folding disorder caused by over 100 distinct mutations in the transthyretin (TTR) gene. In ATTR amyloidosis, protein secreted from the liver aggregates and forms amyloid fibrils in downstream target organs, chiefly the heart and peripheral nervous system. Few a...

Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a multi-system, autosomal dominant protein folding disorder that results from over 100 described mutations in the transthyretin (TTR) gene. Here, we employed a universal gene editing strategy in patient-specific, induced pluripotent stem cells (iPSCs) that allows for the amelioration of all...

Neutrophils and macrophages are critical mediators of innate immunity that share multiple features, including differentiation from common myeloid progenitors that exhibit similar changes in protein expression profiles as they mature into each lineage. Proteins common to both lineages include those critical to phagocyte functions, such as antimicrob...

The GATA family transcription factors GATA2 and GATA1 play reciprocal roles during terminal erythroid and megakaryocytic maturation. GATA2 is expressed early in hematopoiesis and is required for early progenitor cell proliferation and survival. It must be down regulated in order for terminal maturation to occur. In contrast, GATA1 increases in expr...

Neutrophils are blood phagocytes that contain lobulated nuclei, development of which depend on the expression of an inner nuclear membrane (INM) protein called the lamin B receptor (LBR). Loss of LBR expression causes not only hypolobulation of neutrophil nuclei (Pelger-Huët anomaly) but also severe developmental defects in humans (HEM/Greenberg dy...