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November 7, 2019

New Pilot Grants Awarded
By Editorial Staff

The Rockefeller University Center for Clinical and Translational Science (CCTS), along with the Center for Basic and Translational Research on Disorders of the Digestive System (CDDS), and the Shapiro-Silverberg Fund for the Advancement of Translational Research supported 30 pilot projects out of a total of 56 applications that were submitted this year.  CCTS Clinical Scholars received 10 pilot awards.  This year’s total of $1,020,784 awarded brings the grand total of pilot project funding to $9,948,712 since the program began under the initial CTSA grant in 2006. A total of 480 different pilots have been funded to 46 different laboratories.
Support from the Center for Clinical and Translational Science

Pilots Projects Led by CCTS Clinical Scholars

Tobias Becher, MD (Cohen Lab): Role for QSOX1 in the Regulation of Blood Pressure. Obesity is associated with cardiovascular disease, the leading cause of death in the United States. In preliminary studies, the Cohen Lab have identified the fat-secreted protein quiescin sulfhydryl oxidase 1 (QSOX1) as a potential mediator of obesity-associated hypertension. This pilot project aims to understand how QSOX1 may regulate vascular function and contribute to the development of hypertension.
Dana Bielopolski, MD, PhD (Coller Lab): Translational Characterization of Blood Pressure Changes Following Dietary Modification – From Nutrition through Electrolytes to Exosomes. Uncontrolled hypertension is a significant cause of morbidity and mortality, which can be modified by specific diets, such as the DASH diet, which reduces sodium and increases potassium intake. The response to nutritional changes is inconsistent and the mechanism is poorly understood. This pilot project’s goal is to understand the mechanism by hospitalizing volunteers with mild hypertension, feeding them a DASH diet menu and examining and analyzing their clinical and laboratory data, including urinary exosomes.

John Frew, MD (Krueger Lab): Assessment of Inflammatory Mediators in Hidradenitis Suppurativa. This pilot project aims to establish baseline knowledge of immune status (i.e., histological cell infiltrate, tissue cytokine milieu, mRNA gene expression, tissue microbiome metabolomic profile, and adipose tissue analysis) from skin samples of patients with Hidradenitis Suppurativa (HS) and their relation to disease activity and comorbidities compared to healthy control patients. This pilot project builds on results from a 2018 pilot award which led to the identification of IL-17C as a novel cytokine secreted from epithelial keratinocytes of the epidermis and dermal tunnels, as well as the identification of psuedo-psoriasiform epidermal hyperplasia and epidermal recapitulation in the lining of epithelialized tunnels of HS.
David Knorr, MD, PhD (Ravetch Lab): Vaccine immunity in Chronic Lymphocytic Leukemia) and Small Lymphocytic Lymphoma (CLL/SLL)  and the Effect of Bruton’s Tyrosine Kinase Inhibition. The cellular mediators of human immunity to infection remains poorly defined as the majority of our knowledge in this field has come from inherited germline deficiencies or murine models. Patients with cancer are particularly susceptible to infections both intrinsically from their disease as well as due to immunosuppressive drugs they may receive as part of their anti-cancer therapy. More recently, targeted therapies for chronic leukemias (e.g. CLL/SLL) have led to deep remissions and improved survival in this patient population. However, infection remains a significant cause of morbidity and mortality. In CLL/SLL, targeting Bruton’s tyrosine kinase is an effective therapy against malignant B cells, but the mechanisms by which it alters normal B cell immunity are less clear. Thus, this proposal aims to define the intrinsic immune defects in patients with CLL/SLL as well as determine the mechanisms by which BTK inhibition alters the normal humoral response to vaccination.

Rochelle Maxwell, MD (Smogorzewska Lab): Characterizing the Role of the Fanconi Anemia DNA Repair Pathway in the Pathogenesis of Squamous Cell Carcinoma. Persons with Fanconi anemia (FA) have a higher incidence of squamous cell carcinoma (SCC) than the general population.  They develop SCC at a younger age, their tumors are more aggressive, and they have higher morbidity and mortality from the disease. This project aims to investigate the specific mechanisms that underlie the development and progression of SCC in the setting of FA, with the long term goal of developing interventions that may improve clinical outcomes.

Rachel Niec, MD, PhD (Fuchs Lab): Exploring Lymphatic Capillaries as Regulators of the Intestinal Stem Cell Niche. Maintenance of the intestinal barrier epithelium is achieved by long-lived tissue stem cells that have the remarkable capacity to self-renew and give rise to differentiated progeny to fuel this rapidly dividing tissue. These stem cells rely on localized niche signals for their maintenance, differentiation, and environmental responsiveness. Using this pilot award, we will employ three dimensional deep imaging and transcriptional profiling to examine the colonic stem cell niche in health and in inflammatory bowel disease with the goal of identifying new therapeutic targets for regenerative medicine and inflammatory disease.

Yael Renert Youval, MD (Krueger Lab): A Pilot Study of Safety and Biomarkers of Ustekinumab for Cicatricial Alopecia. Primary cicatricial alopecias (CA) are an increasingly common, progressive, scarring disease, resulting in permanent hair-loss, severely affecting quality-of-life. The mechanisms of CA are poorly understood. There are no approved therapies for these conditions and treatment options are unsatisfactory. In a setting of an open-label clinical trial, we will assess samples of skin and blood from CA patients by molecular techniques to investigate the mechanisms of inflammation and scarring at baseline and during treatment with ustekinumab. These findings will help to identify new treatment targets and direct further investigation for the development of new therapies for these disfiguring diseases.

Tukisa Smith, MD, MS (Breslow Lab): Contact Activation in Common Variable Immunodeficiency (CVID). The contact system, a well-characterized serine protease cascade, generates pro-inflammatory mediators and is implicated in key host innate and adaptive immune responses. Although activation of this pathway has been observed in various inflammatory diseases, the contact system is understudied in the most common primary immunodeficiency known as combined variable immunodeficiency (CVID), in which 25-30% of patients develop inflammatory complications despite standard care. This pilot project involves the study of contact system biomarkers in CVID patients, with and without inflammatory complications, with the goal of identifying patients that might benefit most from therapeutically targeting this pathway.

Ying Wang, MD, PhD (Birsoy Lab): Regulation of Erythropoiesis by Mitochondrial Carrier Protein SLCNo5A39. Anemia is a common disease of red blood cell (RBC) deficiency and is a major cause of morbidity; thus understanding how RBCs mature is important.  This pilot award aims to determine how SLC25A39, the orphan mitochondrial solute carrier protein, coordinates cellular metabolism to promote RBC maturation.  This study could provide new insights into the cellular processes of RBC maturation and thus will define new therapeutic strategies to ameliorate erythroid marrow failure and anemia.

Jeffrey Wong, MD, PhD (Ravetch Lab): CD40 Agonism for the Treatment of  Bladder Cancer. Non-muscle invasive bladder cancer (NMIBC) is an area of significant unmet clinical need, with a large affected patient population, high rates of recurrence and progression, and limited salvage therapy options aside from radical cystectomy. A novel immunotherapy approach is proposed based on the agonism of CD40, an immune-stimulatory receptor centrally involved in activating antigen-presenting cells and downstream anti-tumor immunity to investigate locally delivered CD40 agonist therapy in a clinically relevant and highly translatable approach. This pilot study will help define the therapeutic potential of CD40 agonism and support an IND amendment for intravesical treatment of NMIBC with our antibody candidate, which recently began phase I evaluation at Rockefeller University for intratumoral treatment of patients with solid tumor cutaneous metastases.
Pilots Projects Led by Faculty and Postdoctoral Fellows

David Buchholz, PhD (Hatten Lab): Modeling Ataxia-Telangiectasia with Induced Pluripotent Stem Cell-Derived Purkinje Cells. Ataxia-telangiectasia (A-T), caused by mutations in the ATM gene, results in cerebellar degeneration, increased susceptibility to cancer and immune deficiency. Mice with Atm mutations do not have cerebellar degeneration, making this aspect of the disorder difficult to study. This pilot project aims to generate a model system to study human cerebellar Purkinje cells with the ATM mutation, differentiated from induced pluripotent stem cells derived from A-T patients.

Zu-Lin Chen, MD, PhD (Strickland Lab): Specific Blocking Antibodies against High Molecular Weight Kininogen as a Potential Novel Therapy for Hereditary Angioedema. Hereditary angioedema (HAE) is a disease characterized by recurrent tissue swelling that can be life-threatening. It is mainly caused by the release of bradykinin, a peptide cleaved out of high molecular weight kininogen (HK). We generated antibodies specific to cleaved and uncleaved forms of HK, and we will use these to block bradykinin release from HK in vivo. We will determine whether these specific antibodies have the potential to be developed for treatment of HAE and other bradykinin-induced pathologies.

Maria De Obaldia, PhD (Vosshall Lab): Discovery of Human Skin Volatiles that Promote Mosquito Attraction to Humans. Dr. Obaldia is studying why the yellow fever/Zika vector mosquito, Aedes aegypti, prefers to bite some people over others.  We have identified human subjects who are uniquely attractive or unattractive to mosquitoes in laboratory assays. The goal of my pilot award is to perform chemical analysis to identify specific skin odors that make some humans “mosquito magnets.”

Yu-Ling Lee, PhD and Keiichi Ito, PhD (Roeder Lab): Functional Study of E2A-PBX1 Driven Leukemogensis and Potential Clinical Significance for Targeting PD-L1. Based on our biochemical and cell-based assays implicating the importance of MED1/Mediator for the maintenance of E2A-PBX1 fusion driven leukemia, our aim is to address the functional significance of this insight in vivo. We will (i) employ a mouse genetic approach to test the role of MED1 in E2A-PBX1 driven leukemia and (ii) pharmacologically inhibit genes that are directly controlled by E2A-PBX1-MED1 pathway. The goal of our study is to extend mechanistic and functional understanding of E2A-PBX1 driven leukemia and to provide therapeutic approaches against this disease.

Isaac Marin-Valencia, MD, MS (Hatten Lab): Mechanisms and Therapies for Cerebellar Maldevelopment in Pyruvate Dehydrogenase Deficiency.   Mitochondrial disorders are the most common inborn errors of metabolism. These conditions frequently involve the developing brain, in particular, the cerebellum that mediates major disability in patients. This proposal aims to identify mechanisms that underlie cerebellar disruption in the context of defective mitochondria and apply effective therapies accordingly. This project will focus on the prototypical mitochondrial disease with cerebellar involvement, pyruvate dehydrogenase deficiency (PDHD). Preliminary data from a mouse model of PDHD reveal that glucose metabolism in the cerebellum is impaired, and that proliferation and migration of granule cells (GC) is compromised, leading to cerebellar hypoplasia. The central hypothesis is that PDHD disrupts cerebellar formation by limiting GC development due to impaired glucose metabolism. Two aims are proposed: 1) To elucidate developmental processes that underlie the cerebellar disruption, and 2) To identify metabolic mechanisms relevant to cerebellar disease. This proposal is significant because it will advance the understanding of how mitochondrial disorders cause cerebellar disease. It is innovative because it combines advanced techniques to tackle previously unanswerable questions. Long-term, this project will set the basis to potentially approach any neurodevelopmental manifestation of any mitochondrial disease.

Erin Norris, PhD (Strickland Lab): Development of ELISA for Cleaved High Molecular Weight Kininogen as a Diagnostic Tool for Alzheimer’s Disease. The Alzheimer’s disease (AD) peptide, beta-amyloid, can activate the contact system, launching thrombotic and inflammatory pathways. The inflammatory arm leads to cleavage of high molecular weight kininogen (HK), which is found at higher levels in the plasma of AD patients compared to non-demented individuals. We generated HK-specific antibodies to develop a sandwich ELISA that will quantify the levels of intact and cleaved HK in plasma, serving as a way to stratify AD patients with vascular pathology. This tool may also lead to specific therapeutic approaches to delay disease progression.  

Jean-Pierre Roussaire, PhD (Greengard Lab): Single-cell Profiling of Preclinical Alzheimer's Disease For Identification Of Drivers of Neurodeneration. The aim of the study is to generate a high-quality reference dataset of gene expression in the neurons most vulnerable to Alzheimer’s Disease, at very early stages of their pathology. For that, we are performing state-of-the-art single-nucleus sequencing on human postmortem tissue. This dataset, in addition to previous system-level analysis we made of these neurons, will allow us to identify therapeutic targets for treatments to block neurodegeneration in Alzheimer’s Disease.

Sanford Simon, PhD (Simon Lab): Patient Partnership to Identify Cause of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma. Fibrolamellar heptatocellular carcinoma is a rare, usually lethal, liver tumor that afflicts adolescents and young adults. A frequent cause of death is hyperammonic encephalopathy. Given that fibrolamellar is a liver tumor, most treatments involve lactulose, the standard treatment for such tumors. While this works for other liver pathologies, it inevitably leads, in the case of fibrolamellar, to coma and death. Our analysis of the blood and urine levels of the patients suggests a disruption of the urea cycle in fibrolamellar, or in a subset of these patients, which can be treated by sodium benzoate. Our analysis of the transcriptome and proteome of the tumor tissue suggest that we can identify the presence of this disruption and its molecular basis. Success in doing so would inform other therapeutics and save lives.

Support from Center for Basic and Translational Research on Disorders of the Digestive System

Jingyi Chi, BS (Cohen Lab): Molecular regulation of the crosstalk between adipocytes and the sympathetic nervous system in adipose tissue by S100B. The goal of this pilot project is to clarify the molecular mechanism underlying the interaction between beige adipocytes and sympathetic nerves. Insights from this project may suggest novel approaches to prevent and treat obesity.

Gregory Donaldson, PhD (Mucida Lab) Immunoglobulin A Regulation of the Gut Microbiota During the Emergence of Inflammation-Driven Gastrointestinal Cancer. The project investigates how intestinal B cell responses are involved in maintaining a healthy mucosal microbiome, and how this affects downstream immune responses in the initiation and progression of colorectal cancer. This may open up new avenues of treatment or prevention through manipulations of the gut bacterial community for anti-inflammatory or anti-tumor functionality.

Dennis Hsu, MD (Tavazoie Lab) Metabolism-Directed Treatments Using Codon-Based Mutational Signatures in Colorectal Cancer. Our project proposes to use codon-based mutational signatures to identify metabolic vulnerabilities in colon cancer. The goal of this research would be to find a way to use data that is already commonly collected from cancer patients (i.e. next generation sequencing of tumor DNA) and use these data to find patients who might benefit from metabolism-directed therapies. We will test our predictions using mouse models and cell lines that are predicted to be sensitive and resistant, with the hopes that a positive result can be translated into clinical studies down the road.

Eleftherios Michailidis, PhD (Rice Lab) Single-cell Transcriptomics of Human Hepatocytes in Response to Hepatitis B Virus Infection and Interferon Treatment. Chronic carriers of hepatitis B virus (HBV) are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Our proposed work will characterize the hepatocyte transcriptome in response to HBV infection and will provide insights into the curative potential of interferon α treatment. These studies will reveal suitable targets for novel and improved anti-HBV therapies.

Ryan Moy, MD, PhD (Tavazoie Lab) Unraveling the Mechanisms Regulating Gastric Cancer Metastasis to the Liver. Metastatic progression is the primary cause of death in gastric cancer, and the liver is one of the most common sites of metastasis. Using in vivo selection, we have generated human and mouse gastric cancer cells with enhanced ability to metastasize to the liver. We have identified a set of genes that are up-regulated or down-regulated in highly liver metastatic gastric cancer cells, and we will use CRISPR/Cas9 to test the function of these genes in in vivo metastasis assays using cell lines and patient-derived xenograft models.

Bernardo Sgarbi Reis, PhD (Mucida Lab) Characterizing tumor–infiltrating gd T cells in Colon Cancer. Colorectal cancer (CRC) is one of the most common and deadly cancers in the US. The role of intraepithelial lymphocytes (IELs) in the development and progression of CRC is still unclear. My proposal will apply novel tools and concepts from the field of mucosal immunology to elucidate the role of TCRgd+ IELs in CRC."

Support from the Shapiro–Silverberg Fund for the Advancement of Translational Research

Jose Aléman, MD, PhD (Breslow Lab): The Time-Restricted-feeding Effects on Inflammation and Obesity (TRIO). Study Subtitle: The Impact of Early Time Restricted Feeding on Metabolism And Inflammation in Obesity. Time-Restricted Feeding (TRF), a form of intermittent fasting, shows great promise as a novel intervention for addressing obesity and its complications. We propose to conduct a randomized 7 day study in which 10 prediabetic subjects eat all their calories within their first 6 waking hours, followed by 7 days with their usual eating pattern and vice versa. Specifically, we will study how TRF improves glucose metabolism in comparison to systemic inflammation.

Claudia Lorena Buitrago, PhD (Coller Lab): Decoding the Unique Interaction Between Platelet Integrin αIIbβ3 and Cross-Linked Fibrin. The formation of a stable thrombus is accompanied by the generation of thrombin and the conversion of fibrinogen to cross-linked fibrin. While the interaction of platelets with fibrinogen has been well established the interaction with fibrin is less understood despite its clinical relevance. Using human platelets we aim to elucidate the binding kinetics and affinity of αIIbβ3 interaction with fibrin and to make monoclonal antibodies that specifically block fibrin-αIIbβ3 interactions and explore their therapeutic potential.  

Jonatan Ersching, PhD (Victora Lab): B Cell Clonal Evolution in Long-Lasting Germinal Centers During Chronic Hepacivirus Infection.  The main goal of this research proposal is to characterize the dynamics of B cell clones in long-lived GCs during chronic viral infection with a newly described  hepatitis C virus-related hepacivirus. I will test the hypothesis that new B cells invade ongoing GCs over time and eventually replace the initial pool of clones recruited. This will be assessed with fate-mapping strategies combined with parabiosis and single-cell sequencing. Two novel genetic mouse models will also be developed to determine mechanisms of GC clonal replacement and the specific contribution of newly recruited clones to the generation of protective antibodies in serum.
Support from the Shapiro–Silverberg Fund for the Advancement of Translational Research

Seon-Hui Hong, PhD (Rice lab): Interferons Response and Production of Proinflammatory Cytokines and Chemokines from Inherited IFNAR1 Deficient Patient with Vaccine-associated Viscerotropic Disease (YEL-AVD). Although YFV-17D have been safe and effective vaccine to prevent yellow fever virus infection, rare individuals suffer from life-threatening disease including YEL-AVD after vaccination. Using patient-derived induced pluripotent stem cells (iPSCs) from those who have suffered from YEL-AVD, this pilot project will study the underlying mechanism of how the vaccination of YFV-17D can cause YEL-AVD. This research might be helpful to develop new treatment of YEL-AVD and evaluate individual's risk of YEL-AVD before vaccination.

Simon Pelham, MD PhD (Casanova Lab): Identifying the Genetic Susceptibility Underlying Cryptococcosis. S. Pelham’s pilot study will focus on cryptococcus, the fungus that causes severe infections in HIV-immunodeficient and immunosuppressed individuals. In addition to these individuals, there exists subsets of patients who are otherwise healthy, yet suffer from cryptococcosis. We hypothesize that these patients are prone to cryptococcosis due to an inborn error of immunity that selectively disrupts the host defense against cryptococcus. The potential discovery of inherited defect(s) responsible for cryptococcosis could provide insight into the general pathogenic mechanism of cryptococcosis, paving the way for novel treatment strategies, while also revealing novel mechanisms of anti-fungal immunity in natural conditions, a hallmark of human genetic studies.

András Spaan, MD, PhD (Casanova Lab): Human Genetics of Hyper-Inflammatory Responses to Bacterial Infections. Most humans contract minor infections, while only a small minority develops severe disease. Dr. Spaan recently identified a number of patients that suffer from life-threatening hyper-inflammatory responses to bacterial infections due to the same underlying genetic defect. The funding of the pilot award and the facilities of the Hospital will be used to recruit additional patients. The project will provide proof of principle, and will allow for the exploration of innovative therapeutic avenues to treat infectious diseases.