Document text
Principal Investigator: JAMES K CHEN
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $625,036
Funding agency: National Institute of General Medical Sciences
Developmental biology is now both a molecular and systems-level science. Forward- and reverse-genetic
technologies have identified individual genes that regulate tissue formation and contribute to their oncogenic
transformation later in life. High-throughput sequencing has revealed the “omic” features that differentiate cellular
states. Translating this knowledge into mechanistic understanding will require new scientific approaches, and
chemistry can help bridge this gap. Chemical synthesis and protein engineering can empower us to interrogate
tissue biology in new ways, and the resulting technologies and insights can lead to innovative treatments for
human disease. With these goals in mind, our research group has explored the interface of chemistry and
developmental biology. Over the past four years, we have developed an optogenetic system for targeted cell
ablation, identified novel small-molecule inhibitors of Gli transcription factor function, and discovered the first
specific inhibitors of aldehyde dehydrogenase 1B1 (ALDH1B1), a mitochondrial enzyme that is expressed in
multipotent cells of the adult intestine and pancreas and promotes colorectal and pancreatic cancer. We have
also used high-throughput and systems-level approaches to establish a regulatory model for ARHGAP36, a non-
canonical Gli activator that controls motor neuron specification and can induce medulloblastoma.
We now seek to build upon these accomplishments and explore new scientific directions. One focus of our
research program will be the creation of new optogenetic tools that act through inducible allostery rather than
proximity. To facilitate the discovery of such constructs, we have established a transposon-based platform that
recapitulates the evolution of natural photoreceptors. Using this approach, we will develop optogenetic regulators
of the Hedgehog pathway, focusing on light-oxygen-voltage (LOV) domain-functionalized forms of Smoothened
and GLI1. We will elucidate the mechanistic basis of their light-dependent activities, optimize their functionality,
and apply these reagents to study Hedgehog pathway-dependent patterning in zebrafish models. We will also
extend this platform to other developmental pathways such as bone morphogenetic protein signaling. Our
second research focus will be ALDH1 isoforms that are highly expressed in normal stem cells and integral to
tumor initiation and progression. We will investigate the roles of ALDH1B1 in pancreatic cancer and develop
specific inhibitors of ALDH1A3, a cytoplasmic enzyme that promotes breast cancer, melanoma, and
glioblastoma, and other malignancies. In addition, we will pursue small molecules that target ALDH1A1 and/or
ALDH1A2, motivated by the roles of these enzymes in spermatogenesis and their potential as non-hormonal
male contraceptive targets. Collectively, our studies will open new windows into developmental biology and new
doors to clinical therapies.
Terms: <21+ years old><ALDH><ALDH1><ALDH1 enzyme><ALDH1A2><ALDH1A2 gene><Ablation><Adult><Adult Human><Aldehyde Dehydrogenase 1 Family, Member A2 Gene><Basal Transcription Factor><Basal transcription factor genes><Biology><Body Tissues><Bone Morphogenetic Protein Gene><Bone Morphogenetic Proteins><Brachydanio rerio><Breast Cancer><Cancers><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><Chemicals><Chemistry><Clinical><Colorectal Cancer><Cytoplasm><Danio rerio><Development><Developmental Biology><Enzyme Gene><Enzymes><Erinaceidae><Evolution><GLI Family Gene><GLI Family Protein><GLI Protein><GLI gene><GLI1><GLI1 Gene><GLI1 Protein><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Glioblastoma><Glioma Associated Oncogene Homolog 1 Protein><Glioma Associated Oncogene Homolog Protein><Glioma-Associated Oncogene Homolog><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Hedgehogs><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Individual><Intestinal><Intestines><Isoforms><Knowledge><Life><Light><Male Contraception><Male Contraceptive Agents><Male Contraceptives><Malignant Breast Neoplasm><Malignant Melanoma><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Medulloblastoma><Melanoma><Mitochondria><Modeling><Molecular><Motor Cell><Motor Neurons><O element><O2 element><Oncogenesis><Oncogenic><Oxygen><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Pathway interactions><Pattern><Photoradiation><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Progenitor Cells><Protein Engineering><Protein Isoforms><RALDH2 Gene><Reagent><Research><Retinaldehyde-Specific Dehydrogenase Type 2><Role><Science><Signal Pathway><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Specific qualifier value><Specified><Spermatogenesis><Stem Cell like><System><Technology><Tissue Growth><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Translating><Visual Receptor><Zebra Danio><Zebra Fish><Zebrafish><adulthood><aldehyde dehydrogenase 1><aldehyde dehydrogenase 1A2><aldehyde dehydrogenases><bone morphogenic protein><bowel><cancer progression><cellular differentiation><chemical synthesis><contraceptive target><developmental><empowerment><genetic protein engineering><genetic technology><glioblastoma multiforme><glioma associated oncogene 1><glioma associated oncogene family zinc finger 1><human disease><inhibitor><innovate><innovation><innovative><insight><male antifertility drug><malignancy><malignant breast tumor><mitochondrial><motoneuron><motor control><multipotent cell><neoplasm progression><neoplasm/cancer><neoplastic progression><novel><ontogeny><optogenetics><pancreatic malignancy><pathway><programs><protein design><retinal dehydrogenase II><reverse genetics><small molecular inhibitor><small molecule><small molecule inhibitor><social role><spongioblastoma multiforme><stem cell characteristics><stem cells><stemness><tool><transcription factor><tumor initiation><tumor progression><tumorigenesis><voltage>