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Question-Driven Methods and Assays Development and Application for Biomedical Research

 
We develop and use state-of-the-art single-molecule fluorescence microscopy and other advanced imaging techniques, such as multi-color single-molecule localization microscopy, single-molecule FRET, single-molecule tracking, and inclined plane time-lapse microscopy to study specific molecular features and mechanisms of biological systems.  Single-molecule probing methods provide unique information that cannot be obtained with conventional ensemble techniques due to averaging.  A unique advantage of these approaches is based on their ability to detect individual molecules which reveals even low levels and basal level events that are otherwise masked in other methods.These cutting-edge techniques offer new probing capabilities to monitor dynamics of individual proteins and complexes in real time, and image molecules in cells with a resolution of several nanometers. These methods are conceptually groundbreaking and extremely promising in providing a plethora of new information and shedding light on major biological questions.

 
Maintenance of Genomic Integrity, DNA Replication, DNA Damage Response and Repair

 
Genetic instability and impaired DNA replication and repair are key contributors to the development of cancer and severe human syndromes, including neurodegenerative and immunological diseases. DNA is subjected to various genotoxic stresses from regular cellular processes, such as replication and transcription, or from external factors, such as radiation and reactive oxygen species. The cell employs a vast array of enzymes and proteins to survey, detect and maintain the integrity of the genome.  Patient-specific mutations in DNA repair proteins are still the subject of intense study, and related factors are being actively pursued as potential therapeutic targets. However, the specialized steps and processes affected by mutations remain unclear due to the limitations of standard biochemical and cellular methods in measuring critical intermediates and functional features of these repair processes. Despite the emergence of new and advanced cancer treatments, chemotherapy remains the standard-of-care, yet it generally fails to address differential response and mechanisms of resistance that often occurs. Our research program aims to address these unknowns by defining key mechanistic steps of human DNA repair using an array of powerful single-molecule assays and and advanced microscopy methods. This knowledge will be invaluable for developing targeted therapeutic strategies that exploit vulnerabilities in specific DNA repair pathways, ultimately leading to improved treatment outcomes.

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Altered Molecular Architectures and Interactions in Cardiac Disease

 

Cardiac myocytes are highly differentiated, specialized, and compartmentalized cells. Proteins organize in defined microdomains. Slight changes in the position of a protein within its domain can bring about a major disruption in function. Cardiac cells form highly organized specialized cellular junctions which couple cellular communication, signal and force transduction and electrical activity. We use single-molecule microscopy tools to map molecular interactions and architecture of cellular junctions in cardiac cells. 

 
Cancer Associated Signaling Pathways 

 

Tumor cells must adapt in fundamental ways to sustain neoplastic growth and metastasize, yet we have limited understanding of the underlying dynamic processes related to oncogenic drivers and metabolic and apoptotic pathways in cancer cell. This constrains our ability to prevent and efficiently target the emergence of resistance in oncogene driven cancer. We developed several advanced imaging approaches enabling us to define distinct molecular complexes involved in theses pathways and address key questions related to signal-processes and metabolisms 

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