LAIRSON TSRI
Using the tools of chemistry and observing nature's response to molecular structure to generate testable hypotheses about disease relevant biology
RESEARCH INTERESTS
Chemical biology; chemical genetics; regenerative medicine; drug discovery; stem cell biology; neurobiology; cancer biology; glycobiology; organic chemistry; metabolomics; functional genomics and proteomics; enzyme catalysis; molecular evolution
Our research laboratory uses a chemical biology approach to study cell fate- and cell state-determining processes that play a causative role in the progression of human disease. We have ongoing research programs in areas ranging from the selective induction of endogenous stem cell differentiation to the modulation of immunological response within tumor microenvironments. The majority of our research projects involve the use of prospectively isolated primary patient-derived human or engineered rodent cell types, which are used to mimic disease-related process in miniaturized formats. Using the tools of structural diversity and high throughput phenotype-based discovery, typically involving high content imaging or high throughput flow cytometry, small molecules are identified that selectively induce a desired impact on cell fate (e.g., induced differentiation towards a defined lineage) or cell state (e.g., immune checkpoint protein display in response to tumor microenvironment). Validated hit compounds, demonstrated to function via a novel mechanism, are subjected to parallel structure-activity relationship studies and medicinal chemistry-based optimization, as well as target identification and mechanism of action studies. Optimized molecules, possessing suitable pharmacokinetic and target engagement properties, are evaluated in relevant rodent models of disease to assess the relevance of identified mechanisms to disease state. Potential molecular targets are identified using diverse mass spectrometry-based proteomics approaches involving synthesized photo-activatable affinity probe reagents. Downstream mechanism(s) of action are elucidated using standard cell and molecular biology-based techniques. Our research efforts ultimately result in chemistry-based discovery of novel biological mechanisms and the direct enablement of new drug discovery programs.
Using this phenotype-based discovery approach, to date, we have identified novel targets and mechanisms, as well as potential drug candidates, for the treatment of multiple sclerosis and diverse fibrosis-related diseases. Specifically, we have identified agents and targets that enhance oligodendrocyte differentiation/maturation in vitro and in vivo and demonstrated for the first time that this approach was a viable complementary treatment strategy for demyelinating diseases including multiple sclerosis (MS). This approach has also been used to successfully identify multiple novel small molecule inhibitors of myofibrolast differentiation, which were subsequently demonstrated to inhibit disease progression in lung, skin and liver rodent fibrosis disease models. We have additional ongoing phenotype-based discovery research projects involving selective induction of apoptosis in cancer stem cell populations, modulation of immune-checkpoint protein activation within tumor microenvironments and modulation of T cell lineage specification for applications in immuno-oncology and auto-immune diseases.
Chemical biology; chemical genetics; regenerative medicine; drug discovery; stem cell biology; neurobiology; cancer biology; glycobiology; organic chemistry; metabolomics; functional genomics and proteomics; enzyme catalysis; molecular evolution
Our research laboratory uses a chemical biology approach to study cell fate- and cell state-determining processes that play a causative role in the progression of human disease. We have ongoing research programs in areas ranging from the selective induction of endogenous stem cell differentiation to the modulation of immunological response within tumor microenvironments. The majority of our research projects involve the use of prospectively isolated primary patient-derived human or engineered rodent cell types, which are used to mimic disease-related process in miniaturized formats. Using the tools of structural diversity and high throughput phenotype-based discovery, typically involving high content imaging or high throughput flow cytometry, small molecules are identified that selectively induce a desired impact on cell fate (e.g., induced differentiation towards a defined lineage) or cell state (e.g., immune checkpoint protein display in response to tumor microenvironment). Validated hit compounds, demonstrated to function via a novel mechanism, are subjected to parallel structure-activity relationship studies and medicinal chemistry-based optimization, as well as target identification and mechanism of action studies. Optimized molecules, possessing suitable pharmacokinetic and target engagement properties, are evaluated in relevant rodent models of disease to assess the relevance of identified mechanisms to disease state. Potential molecular targets are identified using diverse mass spectrometry-based proteomics approaches involving synthesized photo-activatable affinity probe reagents. Downstream mechanism(s) of action are elucidated using standard cell and molecular biology-based techniques. Our research efforts ultimately result in chemistry-based discovery of novel biological mechanisms and the direct enablement of new drug discovery programs.
Using this phenotype-based discovery approach, to date, we have identified novel targets and mechanisms, as well as potential drug candidates, for the treatment of multiple sclerosis and diverse fibrosis-related diseases. Specifically, we have identified agents and targets that enhance oligodendrocyte differentiation/maturation in vitro and in vivo and demonstrated for the first time that this approach was a viable complementary treatment strategy for demyelinating diseases including multiple sclerosis (MS). This approach has also been used to successfully identify multiple novel small molecule inhibitors of myofibrolast differentiation, which were subsequently demonstrated to inhibit disease progression in lung, skin and liver rodent fibrosis disease models. We have additional ongoing phenotype-based discovery research projects involving selective induction of apoptosis in cancer stem cell populations, modulation of immune-checkpoint protein activation within tumor microenvironments and modulation of T cell lineage specification for applications in immuno-oncology and auto-immune diseases.
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