The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release.

Inositol-1,4,5-triphosphate (IP) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson's disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models.

Uromodulin p.Cys147Trp mutation drives kidney disease by activating ER stress and apoptosis.

Uromodulin-associated kidney disease (UAKD) is caused by mutations in the uromodulin (UMOD) gene that result in a misfolded form of UMOD protein, which is normally secreted by nephrons. In UAKD patients, mutant UMOD is poorly secreted and accumulates in the ER of distal kidney epithelium, but its role in disease progression is largely unknown. Here, we modeled UMOD accumulation in mice by expressing the murine equivalent of the human UMOD p.

Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.

The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells.

Noncoding RNAs regulate NF-κB signaling to modulate blood vessel inflammation.

Cardiovascular diseases such as atherosclerosis are one of the leading causes of morbidity and mortality worldwide. The clinical manifestations of atherosclerosis, which include heart attack and stroke, occur several decades after initiation of the disease and become more severe with age. Inflammation of blood vessels plays a prominent role in atherogenesis.

Inhibition of apoptosis in human induced pluripotent stem cells during expansion in a defined culture using angiopoietin-1 derived peptide QHREDGS.

Adhesion molecule signaling is critical to human pluripotent stem cell (hPSC) survival, self-renewal, and differentiation. Thus, hPSCs are grown as clumps of cells on feeder cell layers or poorly defined extracellular matrices such as Matrigel. We sought to define a small molecule that would initiate adhesion-based signaling to serve as a basis for a defined substrate for hPSC culture.

ETS factors regulate Vegf-dependent arterial specification.

Vegf signaling specifies arterial fate during early vascular development by inducing the transcription of Delta-like 4 (Dll4), the earliest Notch ligand gene expressed in arterial precursor cells. Dll4 expression precedes that of Notch receptors in arteries, and factors that direct its arterial-specific expression are not known. To identify the transcriptional program that initiates arterial Dll4 expression, we characterized an arterial-specific and Vegf-responsive enhancer of Dll4.

MicroRNA control of vascular endothelial growth factor signaling output during vascular development.

The regulated response of endothelial cells to signals in their environment is not only critical for the de novo formation of primordial vascular networks during early development (ie, vasculogenesis), but is also required for the subsequent growth and remodeling of new blood vessels from preexisting ones (ie, angiogenesis). Vascular endothelial growth factors (Vegfs) and their endothelial cell-specific receptors play a crucial role in nearly all aspects of blood vessel growth. How the outputs from these pathways affect and coordinate endothelial behavior is an area of intense research.

Zfhx1b induces a definitive neural stem cell fate in mouse embryonic stem cells.

Inducing a stable and predictable program of neural cell fate in pluripotent cells in vitro is an important goal for utilizing these cells for modeling human disease mechanisms. However, the extent to which in vitro neural specification recapitulates in vivo neural specification remains to be fully established. We previously demonstrated that in the mouse embryo, activation of fibroblast growth factor (FGF) signalling promotes definitive neural stem cell (NSC) development through the upregulation of the transcription factor Zfhx1b.

FGF dependent regulation of Zfhx1b gene expression promotes the formation of definitive neural stem cells in the mouse anterior neurectoderm.

Background: Mouse definitive neural stem cells (NSCs) are derived from a population of LIF-responsive primitive neural stem cells (pNSCs) within the neurectoderm, yet details on the early signaling and transcriptional mechanisms that control this lineage transition are lacking. Here we tested whether FGF and Wnt signaling pathways can regulate Zfhx1b expression to control early neural stem cell development.

Results: By microinjecting FGF8b into the pro-amniotic cavity ex vivo at 7.