CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration.

Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis.

mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme.

Protocol to combine brain sections from multiple mice into a single block for spatial transcriptomic analyses.

Spatial transcriptomics couples visual spatial markers with gene expression levels, but slide space and cost limit the number of samples that can be processed. Here, we present a protocol for mounting brains from multiple mice onto a single capture area of a spatial transcriptomics slide. We describe steps for conjoining frozen hippocampal sections from different brains into a single cryostat block, reducing the quantity of reagents required.

Neurons require glucose uptake and glycolysis in vivo.

Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons.

Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function.

The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines, we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts.

Engineered biomimetic nanoparticle for dual targeting of the cancer stem-like cell population in sonic hedgehog medulloblastoma.

The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood-brain barrier (BBB) penetrance.

Anti-Atherogenic Effect of Stem Cell Nanovesicles Targeting Disturbed Flow Sites.

Atherosclerosis development leads to irreversible cascades, highlighting the unmet need for improved methods of early diagnosis and prevention. Disturbed flow formation is one of the earliest atherogenic events, resulting in increased endothelial permeability and subsequent monocyte recruitment. Here, a mesenchymal stem cell (MSC)-derived nanovesicle (NV) that can target disturbed flow sites with the peptide GSPREYTSYMPH (PREY) (PMSC-NVs) is presented which is selected through phage display screening of a hundred million peptides.

Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms.

Challenges in drug development of neurological diseases remain mainly ascribed to the blood-brain barrier (BBB). Despite the valuable contribution of animal models to drug discovery, it remains difficult to conduct mechanistic studies on the barrier function and interactions with drugs at molecular and cellular levels. Here we present a microphysiological platform that recapitulates the key structure and function of the human BBB and enables 3D mapping of nanoparticle distributions in the vascular and perivascular regions.

Detecting the functional complexities between high-density lipoprotein mimetics.

High-density lipoprotein (HDL) is a key regulator of lipid homeostasis through its native roles like reverse cholesterol transport. The reconstitution of this natural nanoparticle (NP) has become a nexus between nanomedicine and multi-disease therapies, for which a major portion of HDL functionality is attributed to its primary scaffolding protein, apolipoprotein A1 (apoA1). ApoA1-mimetic peptides were formulated as cost-effective alternatives to apoA1-based therapies; reverse-4F (r4F) is one such peptide used as part of a nanoparticle platform.

Tumor Microenvironment on a Chip: The Progress and Future Perspective.

Tumors develop in intricate microenvironments required for their sustained growth, invasion, and metastasis. The tumor microenvironment plays a critical role in the malignant or drug resistant nature of tumors, becoming a promising therapeutic target. Microengineered physiological systems capable of mimicking tumor environments are one emerging platform that allows for quantitative and reproducible characterization of tumor responses with pathophysiological relevance.

Detection of frequency-dependent endothelial response to oscillatory shear stress using a microfluidic transcellular monitor.

The endothelial microenvironment is critical in maintaining the health and function of the intimal layer in vasculature. In the context of cardiovascular disease (CVD), the vascular endothelium is the layer of initiation for the progression of atherosclerosis. While laminar blood flows are known to maintain endothelial homeostasis, disturbed flow conditions including those the endothelium experiences in the carotid artery are responsible for determining the fate of CVD progression.

Nanomedicines for Endothelial Disorders.

The endothelium lines the internal surfaces of blood and lymphatic vessels and has a critical role in maintaining homeostasis. Endothelial dysfunction is involved in the pathology of many diseases and conditions, including disorders such as diabetes, cardiovascular diseases, and cancer. Given this common etiology in a range of diseases, medicines targeting an impaired endothelium can strengthen the arsenal of therapeutics.

Microengineered vascular systems for drug development.

Recent advances in microfabrication technologies and advanced biomaterials have allowed for the development of in vitro platforms that recapitulate more physiologically relevant cellular components and function. Microengineered vascular systems are of particular importance for the efficient assessment of drug candidates to physiological barriers lining microvessels. This review highlights advances in the development of microengineered vascular structures with an emphasis on the potential impact on drug delivery studies.