Awardees Announced for the 2021-22 Columbia Precision Medicine Joint Pilot Grants Program
Jointly awarded by the Columbia Precision Medicine Initiative (CPMI), the Herbert Irving Comprehensive Cancer Center (HICCC), and the Irving Institute for Clinical and Translational Research (Irving Institute), the Precision Medicine Pilot Grants underscore Columbia University’s commitment to supporting diverse, cross-disciplinary research targeting the promise of precision medicine.
Each team will receive a one-year $100,000 grant to support their research. The five projects are being led by principal investigators Ibrahim Batal, MD, associate professor of pathology and cell biology at Columbia University Vagelos College of Physicians and Surgeons (VP&S); Brent Stockwell, PhD, professor and chair of biological sciences at Columbia University; Marie-Pierre St-Onge, PhD, associate professor of nutritional medicine (in Medicine and the Institute of Human Nutrition) at VP&S; Raju Tomer, PhD, assistant professor of biological sciences at Columbia; and Kelley Yan, MD, PhD, assistant professor of medicine and of genetics and development at VP&S.
Congratulations to the winning teams.
The Immunopathology of Donor-Derived APOL1 Nephropathy
Lead Investigator: Ibrahim Batal, MD
Co-investigators: Kevin Gardner, MD, PhD, professor of pathology and cell biology; Barry Freedman, MD, professor of medicine and chief of nephrology at Wake Forest School of Medicine; Iuliana Ionita-Laza, PhD, professor of biostatistics
Kidneys transplanted from Black donors have a shortened survival compared to white donors, which has been attributed to variants of the apolipoprotein L1 (APOL1) gene that is enriched in Black population. Black patients with kidney failure often receive kidneys from Black donors and therefore are more likely to receive kidneys with APOL1 variants that predispose them to early transplant failure. Donor-transmitted APOL1-transmitted kidney diseases are still poorly understood. The team will incorporate precision donor-screening technologies, innovative immunologic studies, and state-of-the-art digital microscopy techniques to better understand the mechanisms of donor-transmitted APOL1-associated kidney diseases, an area ripe for research. This project could improve distribution of donated kidneys in a subset of donors with APOL1 variants, facilitate discovery of more precise treatment, and expand overall understanding of the role of APOL1 in chronic kidney disease at large.
Optimization of Small Molecules that Restore Enzyme Activity to R152H GPX4
Lead Investigator: Brent Stockwell, PhD
Co-investigators: Farhad Forouhar, PhD, associate research scientist at the HICCC; Mohammed N. AlQuraishi, PhD, assistant professor of systems biology
Dr. Stockwell and collaborators have in prior research identified a specific R152H single amino acid alteration in the lipid repair enzyme, called GPX4 that is associated with a severe phenotype involving developmental issues, including a rare progressive disorder called Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) for which there is no cure. In laboratory studies, the researchers uncovered small molecules that can activate the variant, and potentially reverse its developmental damage in patients. However, these novel compounds need to be optimized, in terms of their properties and potency, to allow for testing in animals and ultimately in human clinical trials. In this new project, the team will build on prior results, validate the novel compounds in in an animal model of R152H GPX4, and ultimately serve as corrective drugs to reverse the effect of this variant in patients.
Study of Sleep as an Essential Factor in Aging: Analysis of Biological Biomarkers as Mediators in the Development of Cardiovascular Diseases
Lead Investigator: Marie-Pierre St-Onge, PhD
Co-investigators: Lawrence Honig, MD, PhD, professor of neurology; Rocio Barragan, PhD, postdoctoral research fellow at University of Valencia; Christian Dye, PhD, postdoctoral research fellow in Columbia’s Department of Environmental Health Sciences; and Bin Cheng, PhD, professor of biostatistics
Life expectancy has increased in recent decades, leading to an increase in chronic diseases of old age , like cancer, diabetes or heart disease.. Aging also comes with a decrease in the heart’s ability to contract properly, and research has shown a strong link between aging and the development of heart disease, which remains the leading cause of death worldwide.
Many factors change with age. Among those are changes in the genes that can be used as a “biological clock” to calculate life expectancy. This “biological clock” can be changed by two things the components of cells in the body that carry genetic information and the parts of the genes that are altered by the environment. Dr. St-Onge and team will focus on how our sleep patterns affect biological factors that drive cardiovascular disease. The team will investigate whether sleep reduction causes changes in genes, and how these genetic changes can influence heart health.
Towards Precision Psychiatry: An In Vitro Model of Schizophrenia-associated Network Pathophysiology
Lead Investigator: Raju Tomer, PhD
Co-investigators: Joseph Gogos, MD, PhD, professor of physiology and cellular biophysics, neuroscience and psychiatry (in the Zuckerman Mind Brain Behavior Institute); Sander Markx, MD, PhD, assistant professor of clinical psychiatry
Brain disorders account for 13% of the global disease burden, yet few therapeutic options are available that reduce the disability and mortality associated with these diseases. This is partly due to the immense complexity of the human brain function, which has made it challenging to develop a comprehensive understanding of what drives brain disorders. The team is addressing some of these challenges by building upon the advances in the field of human brain organoids (mini-brains) to develop an in vitro model of patient-specific neural circuit functional deficiencies associated with brain disorders. Their project will focus on two key genetic variants that are the strongest genetic risk factors linked to schizophrenia. For both these genetic conditions, the researchers also have access to cell lines that were derived from human subjects who have previously been diagnosed with schizophrenia, and also have undergone multiple EEG recordings (a test that detects abnormalities in brain waves) for the assessment of seizures. This approach may open possibilities for in vitro modeling and systematic comparative characterization of network-level effects of different mutations linked to psychiatric and neurological disorders, beyond schizophrenia.
Central Memory T cells in the Human Colorectal Cancer Immune Microenvironment
Lead investigator: Kelley Yan, MD, PhD
Co-principal investigator: Arnold Han, MD, PhD, Robert F. Loeb Assistant Professor of Medicine and assistant professor of microbiology and immunology
Although mouse models have proven invaluable in the study of human cancer, no mouse model can completely recapitulate human cancer. Recently, methods to culture and maintain human cancers in the lab have advanced our understanding of human cancer biology. However, because immune cells are present throughout the body and not necessarily localized to tumors, such culture methods have not been applied to the study of immune response to cancers. The team’s preliminary data suggests that it is possible to recapitulate important components of the human immune system with human tumors, including a particularly important immune cell population with therapeutic potential, through in vitro culture. This project will investigate the feasibility of culturing and manipulating human tumor immunity in a self-contained and experimentally tractable culture platform. The aim is to establish the foundation for transformative future experiments with many precision medicine applications.