Awarded Columbia Precision Medicine Joint Pilot Grants

Five research teams at Columbia University have been awarded a 2022 Precision Medicine Pilot Grant to advance the fields of cardiovascular disease, colorectal cancer, rare disease, organ transplant and precision psychiatry. 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. 

Ibrahim Batal, MD,

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. 

Brent Stockwell, PhD

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(link is external and opens in a new window) 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. 

Marie-Pierre St-Onge, PhD

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.  

Raju Tomer, PhD

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. 

Kelley Yan, MD, PhD

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. 

The annual Precision Medicine Pilot Grants have been awarded to five teams of  researchers conducting innovative basic science, translational, and clinical research across multiple diseases. 

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’s commitment to supporting diverse, cross-disciplinary research targeting the promise of precision medicine.

The five winning teams are being led by faculty at Columbia’s Vagelos College of Physicians & Surgeons (VP&S), including: Srilaxmi Bearelly, MD, associate  professor of ophthalmology; Brian Henick, MD, assistant professor of medicine; Chi-Min Ho, PhD, assistant professor of microbiology and immunology; Yufeng Shen, PhD, associate professor of systems biology and of biomedical informatics; and Xuebing Wu, PhD, assistant professor of systems biology and of medicine. The projects being funded are focusing on a range of research, from novel cancer therapeutics to health disparities research. 

The Vagelos Precision Medicine Pilot Grant program is made possible by a generous donation from Roy and Diana Vagelos and is intended to support groundbreaking basic research in the field of precision medicine. Each research team receives $100,000 in funding for one year. The researchers will present their projects at an annual symposium for the precision medicine awards in fall 2022.

Retinal Imaging and Deep Learning to Identify Maternal Risk & Reduce Racial Disparities

Lead Investigator: Srilaxmi Bearelly, MD
Co-Investigators: Ronald Wapner, MD and Andrew Laine, DSc 

Pictures of the back of the eye help us to understand blood vessel changes in disease and health. One of the primary aims of this study is to understand if there are changes in blood vessels in the retina prior to the development of preeclampsia. Preeclampsia is a serious disease of pregnancy that can lead to morbidity and mortality and is more common among racial and ethnic minorities. There is an enormous unmet need to detect preeclampsia at early pre-clinical stages to prevent mortality. The retinal imaging (photo of the back of the eye), is a technique that is non-invasive, requires no dilation, and involves minimal risk to patients. It will be performed on 1,500 pregnant subjects. The goal is to tailor prenatal medical care (prevention, diagnosis, and ultimately treatment of this disease) to the individual patient.

Patient-Derived Organoids to Model and Manipulate Tumor Regulatory Dependencies in Esophageal Adenocarcinoma

Lead Investigator: Brian Henick, MD
Co-Investigators: Andrea Califano, Dr.; Chao Lu, PhD; Hiroshi Nakagawa, MD

Patients with advanced/metastatic esophageal adenocarcinoma (EAC) suffer poor outcomes despite new drug approvals, perhaps because EAC actually represents multiple cancer subtypes not easily distinguishable with conventional techniques. Studying tumor RNA, the Califano laboratory has developed algorithms that can delineate EAC subtypes based on the differential activity of Master Regulator (MR) proteins that mechanistically govern tumor cells’ transcriptional states, amenable to confirmation in model systems. Manipulating MRs genetically or with drugs identified by the CLIA-certified OncoTreat algorithm can help repurpose existing drugs  for use in EAC subtypes on a case-by-case basis. Testing drug efficacy in tumor models by this approach could identify promising new therapies for multiple EAC subtypes simultaneously. Patient-derived organoids (PDOs) are an efficient model system that can recapitulate tumor biology and likelihood of treatment response. The team plans to confirm that human EAC share MRs with their derived PDOs in the Nakagawa laboratory. In the Lu laboratory, they will experimentally knock out MRs predicted to be most essential in each PDO, and finally test a library of drugs to identify those most likely to benefit each EAC subtype.

Direct Visualization of Malaria Parasite Invasion Using Cryoelectron Tomography
Lead Investigator: Chi-Min Ho, PhD
Co-Investigator: David Cobb, PhD

Half the world’s population lives at risk of contracting malaria, which results in more than 400,000 deaths per year. Malaria is caused by malaria parasites that make us sick by invading and replicating inside our red blood cells. In order to enter human red blood cells, the malaria parasite, Plasmodium falciparum, assembles large protein complexes that bind to protein receptors displayed on the surface of the host red blood cell. These large invasion complexes are essential for the parasite to be able to attach to and enter the red blood cell.  The components of these invasion complexes are attractive targets for the development of new anti-malarial therapies and vaccines. Unfortunately, the complexes are short-lived, making them difficult to isolate for structural and functional studies. Drs. Ho and Cobb aim to overcome this obstacle by leveraging recent advances in in situ cryoelectron tomography to directly visualize the full invasion machinery in frozen samples of malaria parasites captured in the act of invading human red blood cells. 

Develop New Computational Methods to Predict Functional Impact of Missense Variants Based on Protein Structure Using Machine Learning

Lead Investigator: Yufeng Shen, PhD 
Co-Investigator: Mohammed AlQuraishi, PhD

Accurate and scalable interpretation of genomic variation is a critical component to realize the full potential of high-throughput sequencing in human genetics and genomic medicine. Missense variants account for most of protein-coding variants with potentially large functional impact; however, most of them do not contribute to disease. The inability to accurately predict their functional impact is a critical hurdle to identifying risk genes in genetic research studies. This project aims to develop new computational methods to predict functional impact of missense variants by leveraging the latest machine learning methods, protein structure, and large genome sequence data of diverse populations. The proposed methods will improve the utility of genome sequencing and enable new discoveries in genetic studies and clinical diagnosis. 

A Special Ribosome in the Heart: Understanding how Mutations in Ribosomal Protein RPL3L Cause Neonatal Dilated Cardiomyopathy by Using Patient-derived iPSCs and Genetically Engineered Mice

Lead Investigator: Xuebing Wu, PhD
Co-Investigators: Steven Marx, MD; Teresa Lee, MD; Mythily Ganapathi, PhD

Mutations in genes can cause severe heart failure in infants. We do not yet fully understand which genes will cause infantile heart failure and what drives it. The research team recently discovered such mutations in RPL3L gene, which encodes a component of the ribosome, the machinery responsible for decoding genetic information and make proteins in every cell. Although initially we thought every human cell has the same ribosome, it turns out in heart and skeletal muscle cells, ribosomes are different from all other human cells as they replace another protein with RPL3L. This project will study the molecular and cellular mechanisms of the special ribosome by using patient-derived stem cells and genetically engineered mouse models. The project’s aim is to help elucidate why heart and muscle cells require a special ribosome, and understand how the mutation causes infantile heart failure.

Five teams of researchers from Columbia University Irving Medical Center (CUIMC) have been awarded pilot grants to fund a diverse set of precision medicine research. 

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 Awards underscore Columbia’s commitment to supporting research targeting the promise of precision medicine, across multiple diseases.

The winning proposals span a wide array of diseases and methods of tackling them, including: uveal melanoma, which occurs in the eye, and the use of exosomal proteins to indicate this cancer; a more streamlined way to identify low- and high-turnover renal osteodystrophy, a bone disorder common in patients with kidney disease; alternative splicing, a human genetic processing mechanism, and how RNA can play a role in that process; hidradenitis suppurativa, a chronic skin inflammatory condition, and the need for increased understanding of the disease and potential treatments; and the role the vaginal microbiome plays in spontaneous preterm birth, a leading cause of neonatal morbidity and mortality.

The Vagelos Precision Medicine Pilot Grant program is made possible by a generous donation from Roy and Diana Vagelos and is intended to support groundbreaking basic research in the field of precision medicine. This year, the program received 34 applications and for the first time leveraged a three-way partnership among the CPMI, the HICCC, and the Irving Institute to aid in new multi-disciplinary collaborations and increasing the number of awards granted.

Biological and Therapeutic Relevance of Exosomes in Uveal Melanoma

Lead Investigator: Richard Carvajal, MD
Co-PIs: Alex Rai, MD; Grazia Ambrosini, PhD

Dr. Carvajal, alongside Drs. Rai and Ambrosini, are working towards identifying a treatment strategy that can prevent the development of metastatic uveal melanoma (UM). UM is a rare melanoma that is distinct from those that start in the pigment producing cells of the skin. Recent analyses of UM patients have shown an increase of proteins contained with exosomes, small vesicles or blisters released from the cell. Cancer-derived exosomes contribute to cancer development and progression, making them both a potential indicator of disease and an opportunity for intervention. The researchers will further assess the role of the exosomes in UM disease progression. The end goal is to identify one or more lead treatment strategies to prevent the development of metastatic disease and devise a clinical trial for patients at high risk for disease recurrence.

Mechanistic Investigation of the Vaginal Microbiome in Different Manifestations of Spontaneous Preterm Birth

Lead Investigator: Tal Korem, PhD
Co-PIs: Anne-Catrin Uhleman, MD, PhD; George Gallos, MD; Joy-Sarah Vink, MD

Spontaneous preterm birth (sPTB) is a leading cause of neonatal morbidity and mortality. The vaginal microbiome – the bacteria and other microorganisms that live in the vagina - is associated with sPTB, but the underlying mechanisms are largely unknown. This stems from the low resolution of current approaches to cataloging the microbes in the vaginal microbiome as well as the oversimplified clinical profiling of sPTB, which ignores the complexity of its pathophysiology. The team will optimize methods for bacterial DNA extraction and perform metagenomic sequencing of vaginal microbiome samples from a well characterized cohort of pregnant women. They will study how the microbiome interacts with the body in the context of sPTB and its clinical presentations, using microbiome analysis methods that provide biological insights to the link between microbial genomes and host outcomes. Their aim is that this research will lead to novel insights regarding the involvement of the microbiome in different manifestations of sPTB, addressing a critical gap in the field.

A microRNA Approach to Identify Renal Osteodystrophy Sub-Type

Lead Investigator: Thomas Nickolas, MD, MS
Co-PIs: Stavroula Kousteni, PhD; Krzysztof Kiryluk, MD, MS

Together, with his collaborators Drs. Kousteni and Kiryluk, Dr. Nickolas is tackling renal osteodystrophy (ROD), a disorder that weakens the skeleton, resulting in bone loss, fractures, and cardiovascular complications. ROD can be classified based on changes in bone turnover rates as high-turnover ROD (markedly elevated) or low-turnover ROD (markedly suppressed. Currently, treatment of ROD focuses on stopping high-turnover ROD, while also avoiding the development of low-turnover ROD that can occur through excessive use of these treatments. There currently is a strong need for a better system of diagnosing  bone turnover rate in patients in order to better manage disease treatment. The team believes circulating fragments of cellular RNA called microRNAs (miRNAs) can assess turnover types in ROD. They are looking to identify miRNA profiles in order to test them as biomarkers of ROD turnover-type, positively impacting the diagnosis and management of ROD.

Deciphering Monogenic and Polygenic Etiologies of a Longitudinal Multi-Ethnic Hidradenitis Suppurativa Cohort

Lead Investigator: Lynn Petukhova, PhD
Co-PI: Suzanne Leal, PhD

Drs. Petukhova and Leal are investigating the chronic skin disease, hidradenitis suppurativa (HS), aiming to find better ways to manage and hopefully prevent it. HS, which typically appears after puberty, causes painful lumps to form deep within the skin. The condition can persist for many years and get worse over time. There is currently a lack of therapies and understanding of HS, causing patients’ needs to remain unmet. The researchers believe that HS has a genetic architecture that is similar to other chronic inflammatory diseases. They will be studying a multi-ethnic group of participants with HS, with a goal of garnering new knowledge about the biological drivers of disease.

Unbiased Screen of Proximal and Distal Splicing Regulatory Elements Towards Drug Discovery

Lead Investigator: Chaolin Zhang, PhD
Co-PI: Samuel Sternberg, PhD

Numerous Mendelian diseases are caused by mutations that disrupt individual genes and could potentially be treated by modulating gene expression to restore normal protein production. A level of molecular regulation called alternative splicing occurs ubiquitously in human genes and frequently generates a combination of RNA isoforms that code for proteins or are noncoding. Modulation of alternative splicing using synthetic genetic strings called antisense oligonucleotides (ASOs) to target splicing regulatory elements has recently emerged as a powerful means of increasing gene expression levels. For example, SPINRAZA is an FDA-approved ASO drug that targets the SMN2 gene to treat spinal muscular atrophy. A critical challenge, however, is pinpointing the most effective regulatory RNA elements that can be targeted to modulate splicing. Drs. Zhang and Sternberg are proposing a high-throughput screening strategy to do just that—to exhaustively identify splicing-regulatory elements for any gene.

Five teams of researchers from Columbia University Irving Medical Center have been awarded pilot grants to fund a diverse set of precision medicine research.
 
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 Awards underscore Columbia’s commitment to supporting research targeting the promise of precision medicine, across multiple diseases. The five teams will each receive $100,000 in funding for one year.
 
The Roy and Diana Vagelos Precision Medicine Pilot Awards are a cornerstone of the CPMI mission: to establish world class academic research centers of excellence to build precision medicine as a basic and applied science at Columbia. Seeding basic research in precision medicine with these awards is an efficient way of converting this money to external research grants and we look forward to this return on investment in due course.
 
The three winning Vagelos proposals reflect the high standard and the broad base of precision medicine basic science research being conducted and conceived at Columbia. They cover research into the role of the vaginal microbiome in premature births; the skin disease hidradenitis suppurativa; and a high-throughput screening strategy to identify splicing-regulatory elements for any gene.
 
Roy and Diana Vagelos Precision Medicine Pilot Awards:
 
“Mechanistic Investigation of the Vaginal Microbiome in Different Manifestations of Spontaneous Preterm Birth”; Lead Investigator: Tal Korem, PhD; Co-PIs: Anne-Catrin Uhleman, MD, PhD; George Gallos, MD; Joy-Sarah Vink, MD
Spontaneous preterm birth (sPTB) is a leading cause of neonatal morbidity and mortality. The vaginal microbiome is associated with sPTB, but the underlying mechanisms are largely unknown. This stems from low taxonomic resolution attainable from 16S rRNA amplicon sequencing, and from the oversimplified clinical profiling of sPTB, which ignores the heterogeneity in its pathophysiology. Dr. Korem and his lab will optimize methods for bacterial DNA extraction and perform metagenomic sequencing of vaginal microbiome samples from a deeply-phenotyped cohort of pregnant women. They will study host-microbiome interactions in the context of sPTB and its underlying etiologies, using microbiome analysis methods which raise mechanistic insights regarding microbial growth rates, genomic variation, and predicted metabolite production. They intend to validate promising hypotheses in vitro and by metabolomic analysis of a subset of samples, and their aim is that this research will lead to novel insights regarding the involvement of the microbiome in different manifestations of sPTB, addressing a critical gap in the field.
 
“Deciphering Monogenic and Polygenic Etiologies of a Longitudinal Multi-Ethnic Hidradenitis Suppurativa Cohort”; Lead Investigator: Lynn Petukhova, PhD
Drs. Petukhova and Leal are investigating the chronic skin disease, hidradenitis suppurativa (HS), aiming to find better ways to manage and hopefully prevent it. HS, which typically appears after puberty, causes painful lumps to form deep within the skin. The condition can persist for many years and get worse over time. There is currently a lack of therapies and understanding of HS, causing patients’ needs to remain unmet. The researchers believe that HS has a genetic architecture that is similar to other chronic inflammatory diseases. They will be studying a multi-ethnic group of participants with HS, with a goal of garnering new knowledge about the biological drivers of disease.
 
“Unbiased Screen of Proximal and Distal Splicing Regulatory Elements Towards Drug Discovery.”; Lead Investigator: Chaolin Zhang, PhD; Co-PI: Samuel Sternberg, PhD
Numerous Mendelian diseases are caused by mutations that disrupt individual genes and could potentially be treated by modulating gene expression to restore normal protein production. A level of molecular regulation called alternative splicing occurs ubiquitously in human genes and frequently generates a combination of RNA isoforms that code for proteins or are noncoding. Modulation of alternative splicing using synthetic genetic strings called antisense oligonucleotides (ASOs) to target splicing regulatory elements has recently emerged as a powerful means of increasing gene expression levels. For example, SPINRAZA is an FDA-approved ASO drug that targets the SMN2 gene to treat spinal muscular atrophy. A critical challenge, however, is pinpointing the most effective regulatory RNA elements that can be targeted to modulate splicing. Drs. Zhang and Sternberg are proposing a high-throughput screening strategy to do just that—to exhaustively identify splicing-regulatory elements for any gene.
 
Herbert Irving Comprehensive Cancer Center Award:
 
"Biological and Therapuetic Relevance of Exosomes in Uveal Melanoma"; Lead Investigator: Richard Carvajal, MD; Co-PIs: Alex Rai, MD; Grazia Ambrosini, PhD
Dr. Carvajal, alongside Drs. Rai and Ambrosini, are working towards identifying a treatment strategy that can prevent the development of metastatic uveal melanoma (UM). UM is a rare melanoma that is distinct from those that start in the pigment producing cells of the skin. Recent analyses of UM patients have shown an increase of proteins contained with exosomes, small vesicles or blisters released from the cell. Cancer-derived exosomes contribute to cancer development and progression, making them both a potential indicator of disease and an opportunity for intervention. The researchers will further assess the role of the exosomes in UM disease progression. The end goal is to identify one or more lead treatment strategies to prevent the development of metastatic disease and devise a clinical trial for patients at high risk for disease recurrence. 
 
Irving Institute for Clinical and Translational Research Award:
 
“A microRNA Approach to Identify Renal Osteodystrophy Sub-Type”; Lead Investigator: Thomas Nickolas, MD, MS; Co-PIs: Stavroula Kousteni, PhD; Krzysztof Kiryluk, MD, MS
Together, with his collaborators Drs. Kousteni and Kiryluk, Dr. Nickolas is tackling renal osteodystrophy (ROD), a disorder that weakens the skeleton, resulting in bone loss, fractures, and cardiovascular complications. ROD can be classified based on changes in bone turnover rates as high-turnover ROD (markedly elevated) or low-turnover ROD (markedly suppressed. Currently, treatment of ROD focuses on stopping high-turnover ROD, while also avoiding the development of low-turnover ROD that can occur through excessive use of these treatments. There currently is a strong need for a better system of diagnosing bone turnover rate in patients in order to better manage disease treatment. The team believes circulating fragments of cellular RNA called microRNAs (miRNAs) can assess turnover types in ROD. They are looking to identify miRNA profiles in order to test them as biomarkers of ROD turnover-type, positively impacting the diagnosis and management of ROD.

We are pleased to announce the winners of the 2^nd Roy and Diana Vagelos Precision Medicine Pilot Awards. We were impressed with the response and with the broad range of proposals from Columbia faculty. The standard of the 34 applications we received was very high, and investigators came from all Columbia campuses. Thanks to all who submitted proposals and to those who participated in the review process.
 
The Roy and Diana Vagelos Awards are a cornerstone of the CPMI mission: to establish world class academic research centers of excellence to build precision medicine as a basic and applied science at Columbia. Seeding basic research in precision medicine with these awards is an efficient way of converting this money to external research grants and we look forward to this return on investment in due course.
 
The three winning proposals reflect the high standard and the broad base of precision medicine basic science research being conducted and conceived at Columbia. They cover epilepsy research; neuro oncology research; and developing a synthetic cell communication tool for tissue engineering.
 
The winning proposals are:
1. Development of novel therapies for STXBP1 encephalopathy.
Michael Boland Ph.D. Dept of Neurology, Institute for Genomic Medicine; Wayne Frankel Ph.D. Dept of Genetics & Development; Sophie Colombo, Sabrina Petri, IGM
 
Mutations in STXBP1 result in a disorder characterized by infantile epilepsy, severe cognitive impairment, and slow progression in GI and motor development. Medications may control seizures, but have no effect on other aspects of development. In children with only one functioning copy of the gene, there is no correlation between severity of seizures and cognitive impairment suggesting that separate mechanisms are involved.  We will study human neuronal and mouse models of STXBP1 haploinsufficiency at the organism, neuronal network, and cellular level in order to identify the most robust features for testing therapies. Screening will be performed on human neuronal networks, and brain region-specific mouse neuronal networks in an effort to identify neuroactive, FDA-approved compounds that correct defects.  We will also develop and test two different gene therapy approaches for correcting associated developmental phenotypes.
 
2. Molecular characterization of gliomas under immunotherapy.
Raul Rabadan PhD, Dept of Bioinformatics; Systems Biology; Fabio Iwamoto MD, Dept of Neurology (Neuro-oncology division); Junfei Zhao, PhD.
 
Glioblastoma is the most common and most aggressive primary brain tumor in adults, with extremely poor prognosis.  While these patients have infrequent tumor responses to immunotherapies compared to melanoma and non-small cell lung cancers, 10% of patients showed limited positive responses. We are extending our current efforts in the molecular characterization of these patients  by extensive profiling the genome of the tumor and the surrounding immune cells of a cohort of IDH1 mutant gliomas treated with immunotherapies after standard treatment. These tumors have been reported to have very high rates of mutations (hypermutation), a genomic characteristic that have been associated to response to immunotherapies. Our work  will identify novel molecular markers of response to immunotherapies by studying specific cohort of these patients treated at Columbia University. 
 
3. Exploiting the basic mechanism of Notch activation to develop new diagnostic, therapeutic and tissue engineering tools for precision medicine.
Gary Struhl PhD; Paul Langridge PhD. Dept of Genetics and Development (in Neuroscience); Zuckerman Mind Brain Behavior Institute
 
Synthetic biology involves engineering cells so that they perform useful tasks. An ambitious aim of the field is to customize the behavior of cells so that they form tissues for the repair of wounds, correction of birth defects, regeneration of damaged limbs or creation of organ substitutes. Central to this goal is enabling cells to communicate using tailor-made components. Our research describes the development of a tool for devising and testing this synthetic cell-communication technology. We will establish a system with entirely synthetic cell-communication that functions alongside natural biological processes and determine how these tools can be used to organize cell behavior and alter the morphology of a tissue. In the future such bespoke systems may well be further customized through their application in precision medicine and lead to therapeutic and biotechnological advances that will help fight disease and repair defects. 

We are pleased to announce the winners of the inaugural Roy and Diana Vagelos Precision Medicine Pilot Awards. We were impressed with the response and with the broad range of proposals from Columbia faculty. The standard of the 56 applications we received was very high, and investigators came from all Columbia campuses. Thanks to all who submitted proposals and to those who participated in the review process.
 
The three winning proposals reflect the high standard, the broad base, and the collaborative nature of precision medicine basic science research being conducted and conceived at Columbia:
Two proposals are a collaboration between junior and senior faculty;
Two feature collaboration between investigators on different campuses;
One, a collaboration between basic and clinical researchers.
 
The winning proposals are:
Programmable probiotics for personalized cancer immunotherapy.
Nicholas Arpaia, PhD, Assistant Professor, Dept. of Microbiology & Immunology; Tal Danino, PhD, Assistant Professor, Dept. of Biomedical Engineering

Objectives:
First, engineer probiotic strains that locally release immunotherapeutics along with tumor-specific antigenic peptides within the tumor microenvironment. Investigators will use synthetic biology approaches to engineer genetic circuits using a strain of E. Coli, which will permit selective growth and synchronized lysis within the hypoxic core of a solid tumor, thus allowing for localized release of plasmid-encoded immunotherapeutics and tumor-specific antigens.
 
Second, characterize anti-tumor immune responses following delivery of engineered immunotherapeutic bacteria encoding tumor-specific antigenic peptides, or reported neoantigens. Investigators will quantify antigen specific anti-tumor T cell responses in an animal model and characterize cytokine production, and hypothesize that bacterial co-delivery will enhance anti-tumor immunity.
 
Third, assess the durability and systemic efficacy of anti-tumor responses elicited by engineered bacterial strains. Investigators hypothesize that the locally primed anti-tumor immunity will lead to durable antigen specific immune responses with long lasting eradication of systemic metastases.
 
Future work:
This proposal leverages expertise in synthetic biology and immunology to engineer probiotic strains of bacteria that selectively colonize tumors and elicit systemic, neoantigen-guided anti-tumor immunity. In future studies, investigators will develop methodologies for identifying patient-specific tumor neoantigen repertoires to create personalized bacterial strains for patient- and tumor-specific immunotherapy.

Elucidating the tissue-specific molecular mechanisms underlying disease associations through integrative analysis of genetic variation and molecular network data.
Tuuli Lappalainen, PhD, Assistant Professor, Dept. of Systems Biology; Junior investigator and Core Member, New York Genome Center; Harmen J Bussemaker, PhD, Professor, Dept. of Biological sciences; Dept. of Systems Biology

Objectives:
The first goal is to dissect the molecular mechanisms underlying tissue-specificity of genetic regulatory variants. Using extensive data produced by the Genome Tissue Expression (GTEx) project, which catalogued thousands of genetic associations with gene expression across hundreds of individuals and dozens of human tissues, the investigators will analyze how the cellular environment modifies the effect size of genetic cis-regulatory variants in the human genome. They will also investigate to what extent these regulatory effects can be rationalized in terms of allelic variation in the binding affinity of transcription factors as predicted from the DNA sequence.
 
The second goal is to map network-level regulatory variants that cause protein-level transcription factor activity to vary between individuals. The investigators will infer TF activity based on DNA binding specificity models of human TFs, and use it as a tissue-specific parameter of the cellular environment. They will also map trans-acting genetic variants that affect TF activity (coined ‘aQTLs’ by one of the investigators) in each tissue. It is anticipated that the trans-acting loci identified by this analysis will be of major interest to basic biology researchers, and will also help explain GWAS associations to complex disease.
 
Future work:
This proposal hopes to elucidate which transcription factors are driving the functional impact and tissue specificity of any particular eQTL. Identifying the transcription factors that are upstream regulators of genetic regulatory variants provides a starting point for mapping the environmental stimuli or drugs that modify these transcription factors. Interactions with disease associations can be studied and validated in available large-scale ‘phenome’ data sets. Furthermore, any aQTLs that colocalize with GWAS loci provide important starting points for further mechanistic study.

 
Notch2 polymorphisms as predictors of low β-cell mass and increased type 2-diabetes risk.
Utpal Pajvani, MD, PhD, Herbert Irving Assistant Professor of Medicine, Dept. of Medicine, Endocrinology; Dieter Egli, PhD, Maimonides Assistant Professor of Developmental Cell Biology, Dept. of Pediatrics; Domenico Accili, MD, Russell Berrie Foundation Professor of Diabetes, Dept. of Medicine; Chief of Endocrinology Division; Director of the Columbia University Diabetes and Endocrinology Research Center.

Objectives:
First, use CRISPR to generate null NOTCH2 alleles, on the background of a reporter IPS line encoding GFP in the insulin locus to allow tracking of the cells in vitro and in vivo. After differentiation to β-cells in vitro and in vivo, test the repercussions of loss of NOTCH2 on β-cell biology.
Second, determine the mechanism of reduced NOTCH2 expression and other possible molecular repercussions of the rs10923931 SNP, and determine effects on β-cell Notch activity and downstream effects on β-cell proliferation and maturation.
 
Future Work:
Investigators predict that NOTCH2 T2D risk variants decrease proliferation of pancreatic progenitors and/or fully developed cells due to reduced β-cell NOTCH2 expression, which in turn reduces β-cell Notch activity. Future work will focus on translational studies, to cross-reference individual genomic information to β-cell mass data from PET imaging. In addition, investigators will test whether the NOTCH2 variant is associated with lower insulin/C-peptide in T2D patients, and whether the NOTCH2 variant will predict early need for insulin therapy in susceptible patients.