Breaking New Cell Biology Research

A breakthrough microscopy technique now enables researchers to observe previously unseen molecular processes within genetic material.

The ISAC award provides seed funding for exceptionally innovative, disruptive (high-risk/high-reward) research relevant to the NIDDK Division of Kidney, Urologic, & Hematologic Diseases that has the potential to lead to groundbreaking or paradigm-shifting results that will change the field. The von Blume lab investigates how neutrophils, frontline defenders against infections, are armed with proteins in distinct granule types. Regulated exocytosis activates them for chemotaxis, phagocytosis, and bacteria eradication. Yet, the molecular mechanisms of granule formation are unclear, limiting treatments for neutropenic disorders. The von Blume lab will investigate molecular mechanisms of neutrophil granule biogenesis that could pave the way for powerful therapeutic strategies. This project will be performed in collaboration with Shangqin Guo’s Yale Stem Cell Center lab.

Research Scientist Yeongho Kim and Professor Chris Burd provide their perspective on lipid sorting pathways that constitute the foundation of organelle biogenesis and membrane homeostasis.

Cholesterol is one of the most abundant lipid components of the plasma membrane. When cells are depleted of cholesterol, they respond by making more sphingomyelin, another abundant lipid of the plasma membrane, that binds cholesterol. Cells obtain cholesterol in from the blood plasma in the form of low density lipoproteins (LDL) which are internalized via endocytosis and processed in the lysosome, liberating free cholesterol to be transported to other organelle membranes. We discovered that cells that cannot make sphingomyelin are unable to export cholesterol from the lysosome and as a consequence, the lipids of the plasma membrane are not properly organized. Our results reveal a 'cholesterol-sphingomyelin regulatory axis' that maintains cholesterol and sphingomyelin homeostasis of cellular membranes.

Investigators have developed a technique that makes microscopic specimens 4,000 times larger, letting researchers see fundamental genomic processes that previously were too small to visualize and evaluate hypotheses that until recently were untestable.

Lysosomes are important for clearance of pathogens and turnover of cellular debris. This requires mechanisms to ensure that cells have enough lysosome activity to prevent the accumulation of potentially toxic materials. However, excessive lysosome degradative activity is also a threat to cells as leakage of lysosomal enzymes can damage and kill cells. It is therefore important that cells maintain an optimum level of lysosome activity that balances the need to efficiently clear waste without causing damage. This study identifies the LRRK2 protein as a brake on lysosome degradative activity. While this may normally play a protective function, mutations in LRRK2 that result in an activation of its kinase activity cause Parkinson's disease. This work demonstrates LRRK2 hyperactivation arising from a Parkinson's disease mutation suppresses the degradative activity of lysosomes and identifies the MiT-TFE family of transcription factors of LRRK2-dependent lysosome suppression.

Assemblies of tiny molecular proteins span the membranes that encapsulate our cells, directing cellular activities and regulating the transport of materials and information in and out. Scientists at the Yale Nanobiology Institute have decoded a chemical signal that allows them to capture these biological interactions directly from their natural habitat.

A recently published Yale study explored how cancer cell plasticity — which refers to the ability of cells to adapt their phenotypes in response to environmental signals without undergoing genetic alterations — might impact the development, progression and treatment of cancer.

Super-resolution microscopy can reveal small subcellular structures invisible to classical light microscopes thanks to its tenfold improved resolution (20-70 nm). The broad application of the new technology has however been hampered by the low throughput of these new technologies: in a typical workday, a researcher can image only about 10 mammalian cells. The Bewersdorf and Baddeley labs have now published a next-generation super-resolution microscope which can image 1,000 to 10,000 cells in an automated manner in 24 hours. This enables future, previously inaccessible studies that require the comparison of many experimental conditions or have high demands for sample size.