Stanford ChEM-H solicited seed grant proposals from the Stanford community of postdoctoral fellows for exploratory projects that align with the Institute’s mission. Successful proposals combined the complementary expertise of two or more postdoctoral researchers (including Ph.D. holders, M.D. residents and M.D. clinical fellows) seeking to collaboratively explore a potentially transformative new idea with the support of their mentors. The four proposals selected were each funded with $50,000 for one year.
"Size-based Isolation of Extracellular Vesicles from iPSC-cardiomyocyte for Diagnosis of Cardiomyopathies"
Mark Chandy, Wu Lab
Mehmet Ozen, Demirci Lab
Joseph Wu, Cardiovascular Medicine and Radiology
Utkan Demirci, Radiology
Cardiomyopathy is a severe disease of the heart that leads to heart failure—the heart cannot keep up with the demands of the body and fluid builds up in the lung and body. If a cardiomyopathy is detected early, physicians can start medications and use devices to improve symptoms and prolong life. We propose to search for new biomarkers of heart failure by studying the vesicles secreted from the heart. To do this, we will generate heart tissue from patients using stem cells. We will then utilize an engineering approach to isolate microvesicles and compare their contents with patient blood and identify novel biomarkers to diagnose cardiomyopathy.
"Investigating the Enteric Nervous System Metabolome"
Subhamoy Das, Kaltschmidt Lab
Vijaya Lakshmi Kanchustambham, Zare Lab
Julia Kaltschmidt, Neurosurgery
Richard Zare, Chemistry
Digestion is an important physiological phenomenon facilitated by nerves, muscles, and other gut cells. Various gastrointestinal disorders cause disruption of the normal digestion process and many of these have a neuronal origin. The nervous system that resides within the gut wall is called the enteric nervous system (ENS), also referred as the “second brain”. Understanding the biochemical profile of the ENS is a long-standing open question. While the ENS field has relied heavily on immuno-labeling of peptides and proteins such as neurotransmitters and signaling molecules, studying the entire metabolic profile of the ENS presents a serious challenge that so far has never been met. Speed and consistency limit standard techniques to analyze metabolites over the length of the entire gut tube. Here we propose to use a new, high-throughput technology called DESI-MSI (Desorption ElectroSpray Ionization - Mass Spectrometry Imaging). DESI-MSI can be used to scan tissue micro-sections and acquire the entire metabolic profile of the native tissue via mass spectrometry. This metabolic profile includes neurotransmitters, lipids, small molecules, small peptides, and other metabolites. In this proposal, we aim to scan mouse tissue sections from each portion of the gut (from the beginning of the esophagus to the end of the colon) and create a spatial map of the metabolic signature of the ENS. In the future, this information will drive drug discovery and the development of therapeutics for gastrointestinal diseases.
"Connectome-seq: Unbiased High-throughput Brain Connectome Mapping"
Alina Isakova, Quake Lab
Boxuan Zhao, Ting and Luo Labs
Stephen Quake, Bioengineering and Applied Physics
Alice Ting, Genetics and Biology
Liqun Luo, Biology
The ability of the brain to control our behavior, feelings, and thoughts has long been of a great interest and fascination to scientists. Unveiling the complexity of the brain and particularly its intricate network of connections, controlling various physiological functions of the body, remains one of the biggest scientific challenges of the 21st century. This, however, proved to be a non-trivial task, mainly due to limitations of the current technologies that are unable to capture the brain connectome at the full scale. Here, we set out to address this challenge and create a state of the art technology capable to map extensive networks of neural connections across proximal and distal regions of the brain. Combining the most recent discoveries in the fields of molecular biology and engineering, we will create a trans-synaptic labeling system aimed to effectively tag all synapses in the brain with unique nucleic acid barcodes. Once tagged, the synapses can then be read out by high-throughput sequencing, revealing the identity of neurons involved in the interaction. Profiling a vast number of synapses, we expect to fully map the interactions between various types of neurons and thus reconstruct a global map of connectome linking different brain regions.
"Monitoring Tumor Heterogeneity and Drug Response in Barcoded Patient Derived Organoids Using Multi-omics Single Cell Approach"
Kasper Karlsson, Curtis Lab
Amber Smith, Kuo Lab
Akshay Balsubramani, Kundaje Lab
Kathryn Yost (PhD student), Chang Lab
Christina Curtis, Medicine - Oncology and Genetics
Calvin Kuo, Medicine - Hematology
Anshul Kundaje, Genetics and Computer Science
Howard Chang, Dermatology and Genetics
Pancreatic Ductal Adenocarcinoma (PDAC) is an insidious and deadly malignancy, with the worst 1-year and 5-year survival rates of all cancer types. Poor survival is in part due to our incomplete understanding of tumor heterogeneity, and how tumor sub-clones influence drug response. To increase our understanding of PDAC heterogeneity we will derive organoids from resections of PDAC tumors and make cells unique by integrating a random DNA barcode into the genome of each cell. Since daughter cells inherit the integrated barcode, cells with the same barcode can be defined as a tumor sub-clone. Barcoded cells will be expanded, and drug treated with standard of care drugs for PDAC to identify sub-clone specific response. Single cell sequencing in combination with barcode sequencing will be used to elucidate transcriptome, regulome and genome composition of resistant sub-clones, in order to identify novel biomarkers for sub-clone resistance.