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Research

The cell nucleus surrounds, organizes and mechanically protects the genome. Lamin filament networks and nuclear membrane proteins support and influence most activities in the nucleus, with central and dynamic roles in customizing the 3D spatial organization of individual chromosomes needed for tissue-specific gene silencing. The functions and regulation of nuclear ‘lamina’ networks are an open frontier in biology.

Mutations and deletions in the gene encoding phosphatase and tensin homolog (PTEN) deleted from chromosome 10 are associated with many cancers and autism.  After being recruited to the plasma membrane from the cytosol, PTEN dephosphorylates PIP3 to PIP2 and opposes tumorigenic phosphoinositide 3-kinase signaling. Illustrating the importance of the membrane association of PTEN, we recently discovered a new class of cancer- and autism-associated PTEN mutations that specifically interfere with the membrane association.

Neurons communicate with each other through chemical signals that are released from one nerve terminal (pre-synapse) and received by another (post-synapse). Neurotransmission is fundamental to both mental and physical activities, and it is also essential for the initial wiring and reconfiguration of neural circuits throughout the lifetime of an organism. In addition, defects in neurotransmission play a causative role in neurological disorders. However, our understanding of the process is limited by three main factors: size, speed, and molecular complexity.

Many adult tissues are renewed from small populations of stem cells, which continually replace differentiated cells lost to damage or age.  Since tissue stem cells are highly dependent on signals from their local microenvironments, or niches, understanding how niches work is important for manipulating regeneration.  To answer this question, the Matunis lab combines genetics, live imaging, and genome-wide approaches to understand how the germline and somatic cells in the testis that create and reside in the testis niche cooperatively ensure a lifetime supply of sperm.

As human longevity increases, understanding the mechanisms that drive aging becomes ever more critical. We study the premature aging disorder Hutchinson Gilford Progeria Syndrome to gain molecular insights into aging, focusing on the nuclear scaffold protein lamin A and its proteolytic processing enzyme ZMPSTE24, since mutations in either can cause progeria.

Coronaviruses are enveloped viruses that assemble by budding into the Golgi lumen and then follow the secretory pathway, which is inefficient for such large cargo. These viruses first induce dilation of Golgi cisternae and then modulate the luminal microenvironment to protect virions during their slow trafficking. We are studying the mechanisms by which these perturbations occur to help understand how cells handle other large cargo (e.g. chylomicrons).

Dysfunction of cellular mechanisms maintaining proteostasis leads to accumulation of misfolded proteins and their aggregates, which often results in debilitating human diseases, such as neurodegenerative diseases (ND). Interestingly, those diseases are also frequently coupled with mitochondrial defects. Although proteostasis and mitochondria are individually studied intensively in the context of ND, the relationship between those two are poorly understood.

The Inoue Lab develops molecular tools to visualize and re-program cellular processes, and uses these tools to understand complex signaling networks as well as dynamic subcellular entities. In particular, the Inoue Lab has developed chemically-activated switches and fluorescent sensors to explore the assembly and function of the primary cilium, mechanisms of cell locomotion, and regulation of phagocytosis.

Infective parasites must traverse the mosquito salivary glands to transmit malaria to humans and other animals.  The Andrew Lab is leveraging its findings on the molecules required to form and maintain the Drosophila salivary gland to develop strategies to block malaria transmission.  Shown is an optical section through the distal lateral lobe of a female adult salivary gland stained with DAPI (blue, nuclei), alpha-tubulin (green, cytosol) and wheat-germ agglutinin (red; chitin/O-GlcNAcylated proteins).

To maintain homeostasis, cells need to measure the concentration of molecules such as nutrients, reactants, and products. Eukaryotic cells, whether single-cell fungi or part of a complex human organ, require environmental oxygen for essential reactions. Consequently, cells possess mechanisms to sense and adapt to changes in oxygen supply. The hypoxia-inducible factor (HIF) is a key regulator of these adaptive responses in metazoans.

Among the earliest inputs that cells experienced, mechanical stress (forces) guide and direct behavior of cells, including when they are part of tissues, organs, and organ systems.  These mechanical stresses are propagated through the cell’s skin (the cell cortex), which is a composite material of membrane and cytoskeleton.  Key molecular machinery senses the forces, and through mechanotransduction, the mechanical signals may be converted into biochemical signals, which guide cell behavior. 

Research in the Ewald laboratory starts from a simple question: which cells in a breast tumor are the most dangerous to the patient and most responsible for metastatic disease? To answer this question, we developed novel 3D culture assays to allow real-time analysis of invasion. Briefly, we use enzymatic digestion to isolate thousands of “tumor organoids” from each primary tumor. Each organoid is composed of 200-500 epithelial cancer cells and reflects the cellular heterogeneity of the primary tumor.

Mitochondria play crucial roles in diverse cellular and physiological processes such as energy production, metabolism, intracellular signaling, cell death, development, and immune response. In these functions, mitochondria serve as a bioenergetic power plant and a dynamic signaling hub. It has become increasingly clear that these mitochondrial functions are important for human health, and defects in these processes lead to pathological consequences such as metabolic diseases, cancer, autoimmune diseases, and neurodegenerative diseases.

Biological oscillations are universally found in nature and are critical at many levels of cellular organization. In the model organism we study, the social amoeba Dictyostelium discoideum, starvation-triggered cell-cell aggregation and developmental morphogenesis are orchestrated by periodic extracellular cAMP waves, which provide both gradients for chemotactic migration and signals for development. Repeated occupancy of the G protein–coupled cAMP receptors promotes optimal developmental gene expression, whereas continuous stimulation suppresses the program.

Cytokinesis is a mechanosensitive, fluid dynamical process, and the cytokinesis molecular network is structured like a control system with many feedback loops. The core of this control system is the contractility controller, which has a tremendous dynamic range of force production with about 5-fold coming from myosin II's load sensitivity (reflected in changes in duty ratio) and another 5-7-fold coming from changes in protein concentration. Furthermore, the contractility controller is highly robust, being composed of a group of ‘team-player’ proteins.