Using time-lapse microscopy, we showed that nuclear envelope (NE) formation is mediated by reshaping of the endoplasmic reticulum and not as previously thought by vesicle fusion. Our results answered a long-standing question in the field of nuclear biology and provided a new paradigm for membrane dynamics.
In continuation of this work we recently discovered a remarkable phenomenon whereby the NE becomes transiently ruptured and repaired during interphase in various human cancer cells. Strikingly, NE rupturing was associated with loss of cell compartmentalization and a catastrophic chromosome rearrangement event called chromothripsis and thus might be a source of genomic instability.
Cell differentiation and development
Using Drosophila genetics in combination with imaging and DNA sequencing methods in mouse and human stem cells, we discovered that several NE proteins play an essential role in transcriptional activation of developmentally regulated genes. These findings provided first evidence for a functional role of NE-mediated gene regulation and establish a new framework for studying the spatial organization of the nuclear genome. Most recently, we could show that the nuclear pore protein Nup153 plays a role in stem cell pluripotency through gene silencing.
Protein homeostasis and aging
Initially using the model organism C. elegans followed by metabolic labeling experiments in rats and quantitative mass spectrometry, we discovered long-lived proteins (LLPs) in the NE and on chromatin, which exhibit no or very little protein turnover in the adult brain. Our results reveal a novel aspect of protein homeostasis in the nucleus and suggest that a failure to maintain proper levels and functional integrity of LLPs could be a major contributor to age-related changes in the function of post-mitotic tissues. We plan to decipher the mechanisms by which the functional integrity of these proteins is protected over long periods of time, and determine whether their eventual functional decline contributes to age-related pathologies in the brain.
Hu Cang, PhD
Assistant Professor Waitt Advanced Biophotonics Center Frederick B. Rentschler Developmental Chair
Advances in optical engineering now routinely provide researchers with an unprecedented ability to control, manipulate and detect light. Simultaneously, modern manufacturing and fabrication technologies allow unprecedented insights into a new and virtually uninvestigated nano-world. The Cang Laboratory in the Waitt Advanced Biophotonics Center is focused on taking advantage of both these advances to further enhance our ability to manipulate light as a tool to investigate the basic function of biological systems.
One of our primary research aims is to extend the theory of geometric optics to the nanoscale. The goal of this theoretical work is to design a new and novel lens system whose optical resolution will no longer be limited by the wavelength of light. In principle, this "super lens" will enable an optical microscope to reach the same resolution levels as that of an electron microscope. Previously, our group has designed and fabricated novel nano-structures for biological and medical applications. These have included novel nanoparticles that have enhanced the contrast of Spectroscopy-Optical Coherence Tomography (S-OCT), a technique that holds potential as a diagnostic tool for early cancer detection. In addition, our group has fabricated optical antennas that harvest photons from dye molecules, enhancing their brightness by nearly a factor of 1,000. We hope to use these special antennas to monitor conformational changes in a single protein molecule in real-time. We also plan to integrate these optical antennas with our previously developed single-molecule tracking technology to measure how single proteins function and how they are synchronized with other proteins within the complex three-dimensional environment of a living cell.
We are seeking students or postdocs to join efforts in the development of novel nano-photonics tools for biological and medical studies. Candidates with experience in any of the following areas are highly desired: experimental optics, theoretical or computational optics, and molecular biology or biophysics. Please contact Dr. Hu Cang (firstname.lastname@example.org) for more information.
Björn Lillemeier, PhD
Associate Professor Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis Waitt Advanced Biophotonics Center
One of the central challenges in biology is to elucidate how microenvironments modulate molecular mechanisms and thus global cellular function. The Lillemeier lab studies signal transduction in the plasma membrane of T lymphocytes (T cells) upon their activation by Antigen Presenting Cells (APCs). Major rearrangements of signaling molecules take place during this event, which is most dramatically seen in the formation of signaling microclusters and the immunological synapse (see movie). The lab uses cutting edge super-resolution and dynamic fluorescence microscopy techniques (e.g. PALM and FCCS) in combination with traditional biochemical and molecular biological approaches to study the molecular patterns that regulate and are required for T cell activation and function.
We have found a new type of plasma membrane domains, termed protein islands, and the specific segregation of all membrane-associated proteins within them. These findings inspire a new and unsuspected role for the plasma membrane in the spatio-temporal regulation of T cell activation and membrane biology in general. Specifically, we found that signaling cascades are prearranged into 'building blocks', through the localization of signaling molecule subsets within specific protein islands. Redistribution of these protein islands in response to stimuli can lead to either concatenation and assembly of signal transduction pathways or their dissociation and disassembly. These rearrangements are not diffusion limited but active and directed through cytoskeletal forces and pathway-specific protein-protein interactions.
We welcome students and postdocs to join our lab. For more information please contact Björn Lillemeier at email@example.com.
Axel Nimmerjahn, PhD
Assistant Professor Waitt Advanced Biophotonics Center
The human central nervous system (CNS), which includes the brain and spinal cord, consists of an incredibly diverse set of cells, and each cell type carries out highly specialized functions in cellular networks of dazzling complexity. While much research has focused on understanding the circuits formed by neurons, brain cells called glia are equally pervasive and account for roughly an equal number of cells in the human CNS. Glial cells were long believed to play a merely passive, supportive role in CNS function. However, it is becoming increasingly clear that glia make crucial contributions to CNS formation, operation and adaptation. Additionally, glial cells are involved in practically all CNS injuries and diseases, including viral and bacterial infections, Alzheimer’s and Parkinson’s diseases, cancer and stroke. This makes glia promising targets for future therapeutic interventions.
Axel Nimmerjahn has spearheaded the development of new microscopy techniques to visualize the dynamics of glial cells and their functional cellular interactions in the living CNS. He has worked to shrink the size of microscopes to make them wearable. His tiny microscopes are less than 0.2 cubic inch in size, weigh less than two grams and have allowed him to reveal how cellular activity relates to behavior. Additionally, he has created new tools for cell type-specific staining and genetic manipulation and for analysis of large-scale imaging data. This has allowed him to address long-standing questions regarding the role of glial cells in the intact healthy or diseased nervous system. Resolving these fundamental questions has broad implications for our understanding of CNS function and the treatment of neuroinflammatory and neurological disorders.