Awardees Announced for the 2022-23 Columbia Precision Medicine Joint Pilot Grant 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, 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: Ji-Yeon Shin, PhD, Assistant Professor of Medical Sciences (in Medicine), Columbia University Vagelos College of Physicians and Surgeons (VP&S); Yueqing Peng, PhD, Assistant Professor of Pathology and Cell Biology at VP&S; Kathrin Schilling, PhD, Assistant Professor of Environmental Health Sciences, Columbia University Mailman School of Public Health, and five additional co-PIs; Swarnali Acharyya, PhD, Assistant Professor of Pathology and Cell Biology at VP&S; and Thomas Hays, MD, PhD, Assistant Professor, Pediatrics at VP&S.

 
Congratulations to the winning teams.

Columbia Precision Medicine Initiative (CPMI)

Impaired cellular energetics and lipid metabolism in human iPSC-derived Cardiomyocytes carrying cardiomyopathy-causing mutations in genes encoding nuclear envelope proteins

Investigators: Ji-Yeon Shin, PhD (Principal Investigator); Barry M. Fine, MD, PhD, Hanrui Zhang, PhD

Cardiomyopathy caused by mutations in genes encoding lamin A/C, emerin and LAP1, is a common life-threatening disease without a cure. While the genetic mutations and clinical symptoms of patients with these mutations have been well described, much less is known about how the defects in these proteins alter the physiology of the cardiac cells. It has been difficult to determine the effects of cardiomyopathy-causing gene mutations on human cardiac cells’ physiology due to the lack of proper model system to test. We have established human induced pluripotent stem cell (hiPSC)-derived cardiomyocyte lines in the isogenic background except for precisely edited genetic mutations in the genes encoding the three interacting proteins. The main goal of the project is to examine altered cellular lipid metabolism, mechanical and electrical properties of these mutant-bearing hiPSC-derived cardiomyocytes and engineered heart tissues. The knowledge gained from this study may provide data to elucidate the underlying molecular defects that can be targeted against the cardiomyopathy caused by these mutations.

The impact of sleep fragmentation on memory dysfunctions in neuropsychiatric disorders

Investigators: Yueqing Peng, PhD (Principal Investigator); Gergely Turi, PhD (Co-Principal Investigator)

Sleep fragmentation is a common theme across many neuropsychiatric disorders, such as major depressive disorder (MDD), generalized anxiety disorder, posttraumatic stress disorder (PTSD). Despite the high comorbidity between neuropsychiatric disorders and sleep disturbances, the underlying neural mechanisms linking them remain elusive. In this proposal, we make use of fiber photometry, two-photon calcium imaging, electrophysiology, and mouse genetics to study the effect of disrupted sleep pattern on cognitive dysfunctions such as memory impairment in mouse models of neuropsychiatric disorders. By characterizing the effect of sleep disruption on neuronal functions the work proposed in this research application will expand our understanding of the sleep and cognition functional domains implicated in the pathomechanisms of neuropsychiatric disorders.

Metallomics MISSION: A comprehensive assessment of Metals, ISotopes and SpeciatioN as disease biomarkers and therapeutic targets

Investigators: Kathrin Schilling, PhD*; Ronald Glabonjat, PhD*; Ana Navas Acien, MD, PhD*; Alex N Halliday, PhD#; Hiroo Takayama, MD+; Gervasio A. Lamas, MD^ (Co-Principal Investigators)

*Department of Environmental Health Sciences, Columbia University Mailman School of Public Health; #Columbia Climate School, Columbia University; +Department of Surgery, VP&S; ^Division of Cardiology at Mount Sinai Medical Center, Columbia University

Decades of research proved that non-essential metals are a significant risk factor for cardiovascular disease and diabetes. Metal chelation therapy is a medical procedure that involves the administration of chelating agents to remove non-essential and toxic metals from the body and has shown benefit patients with these diseases. To untangle the molecular underpinnings of metal removal, diverse analytical methods are needed to assess chelation treatment for individual patients. We see that the time is ripe for applying new analytical metallomics techniques with unprecedented accuracy to help solve the most pressing scientific and life-changing challenges in precision research. Our Metallomics MISSION project covers three pillars: total elements, metal isotopes, and element speciation analysis. Metallomics MISSION is a laboratory-clinical collaboration focusing on developing effective therapies for metal burden by tracing metabolic processes, identifying metallomics signatures at the individual-level for cardiovascular disease, and outlining future research directions in precision medicine. 

Herbert Irving Comprehensive Cancer Center (HICCC)

Targeting S100A9 using RA antagonists and nano ligases to treat CNS metastasis in lung cancer

Investigators: Swarnali Acharyya, PhD (Principal Investigator); Henry Colecraft, PhD (Co-Principal Investigator), Cathy Shu, MD; Jeff Bruce, MD; Guy McKhann, MD; Peter Canoll, MD, PhD

Metastasis of the central nervous system (CNS) is a frequent complication in EGFR-mutant lung cancer patients and is associated with accelerated mortality. The proposed studies on precision-targeting of brain metastasis using RA antagonists and nanoligases bring together junior investigator Swarnali Acharyya (Institute for Cancer Genetics, Pathology and Cell Biology and HICCC) and senior investigator Henry Colecraft (Physiology and Cellular Biophysics, and Pharmacology, CUIMC) as co-PIs, and all investigators will focus on precision-guided targeting of CNS metastasis to prolong lung cancer patient survival.

The novelty of the proposed studies includes:

- A new druggable target to treat brain relapse even after patients develop EGFR-therapy resistance based on our published studies (Biswas et al.; Cancer Discovery, 2022).

- Developing new brain-penetrant nanoligases against S100A9 as a novel therapeutic strategy.

- Addresses whether patients with brain and leptomeningeal CNS metastasis can benefit from S100A9/RA inhibition.

- Identifies which patients are at risk by novel companion biomarker analysis who can avoid unnecessary overtreatment and toxicities.

Irving Institute for Clinical and Translational Research

The Genetic Basis of Small for Gestational Age Preterm Birth

Investigators: Thomas Hays, MD, PhD (Principal Investigator); Joshua Motelow, MD, PhD; Caitlin Baptiste, MD

Preterm infants experience a profound burden of morbidity and mortality, and one of the strongest risk factors is small for gestational age (SGA) birth. Multiple causes have been identified (placental insufficiency, infection, maternal co-morbidities), yet these explain a fraction of cases. Several genetic disorders are associated with SGA preterm birth, but the overall genetic contribution is unknown. Work by our group demonstrated a strong association between genetic disorders and related clinical presentations. And we found that de novo loss of function (LoF) variants contribute to pediatric critical illness.

Given this, we hypothesize that genetic disorders account for a significant portion of preterm SGA birth. We will investigate by 1) using the largest, most robust database of neonatal records (the Pediatrix Clinical Data Warehouse) to delineate the epidemiologic factors associated with preterm SGA birth, including common genetic disorders; 2) exome and genome sequencing to determine the prevalence of rare genetic disorders in preterm SGA infants; and 3) screening de novo LoF variants for novel genetic causes.

This work has crucial implications for research and clinical practice including informing the clinical use of genetic testing in preterm SGA infants and studying new avenues for therapy.