Center for Clinical and Translational Science

The Rockefeller University Center for Clinical and Translational Science (CCTS) and the Shapiro-Silverberg Fund for the Advancement of Translational Research supported 24 pilot projects out of a total of 27 applications that were submitted this year.  CCTS Clinical Scholars received 10 pilot awards.  The total awarded for this year is $475,000, which brings the grand total of pilot project funding to $10,988,712 since the program began under the initial CTSA grant in 2006. A total of 530 different pilots have been funded in 48 different laboratories.

Support from the Center for Clinical and Translational Science
Pilots Projects Led by CCTS Clinical Scholars

Amichai Berkovitz (Simon Lab): Genome Wide Association Studies in Fibrolamellar Carcinoma. We are proposing a Genome Wide Association Study (GWAS) for Fibrolamellar hepatocellular carcinoma (FLC). Patients with FLC have a deletion in one copy of one chromosome which results in a fusion gene. We have shown that forcing that deletion, with CRISPR/Cas9, can produce the tumor. We will study the genomes from healthy cells of FLC patients to probe for genetic variations that are associated with these variations in disease behavior and treatment-response. This work could help guide patient management and therapeutics.

Charlie Buffie (Brady Lab): Identification of Intestinal Microbiota-Derived Small Molecules that Modulate Mammalian Toll-Like Receptor Activity. Innate immune signaling via Toll-like receptors (TLRs) influences a broad range of human physiology and disease. Native intestinal commensal bacteria modulate TLR signaling, playing roles in immune defense against intestinal pathogens, autoimmune disease, and vaccine efficacy. However, the repertoire of TLR ligands produced by these bacteria and the precise bacterial sources of such ligands is not known. Here we propose to determine the chemical identity, bacterial sources, and human intestinal abundance of TLR-active metabolites produced by native intestinal bacteria. This work may identify novel metabolites and their parent bacterial strains prevalent among the intestinal microbiota that influence human health through TLRs signaling.

Nicole Cruz (Roeder Lab): Rewiring of the PPARγ Transcriptional Network in Monocytic Acute Myeloid Leukemia (AML). We aim to uncover the pathways involved in the differentiation block of monocytic AMLs hoping that it will inspire the design of successful differentiation therapies for this terrible disease. A reasonable candidate pathway to induce differentiation in AML involves signal initiation through generation of the PPARγ:RXR heterodimer. This proposal aims to fill this gap by applying several genomic and biochemical techniques to unearth the key players in the “rewired and leukemogenic PPARγ transcriptional network”.
 
Katherine Knorr (Ravetch Lab): Defining Expression of Fc Receptors in Acute Myeloid Leukemia. Despite nearly five decades of research aimed to advance therapy for acute myeloid leukemia (AML), many patients do not respond to chemotherapy or newly approved targeted agents. Primary refractory disease as well as relapsed disease are not only difficult to treat but confer dismal patient prognosis with overall survival measured in months. There is a clear need for novel or alternative therapeutic approaches for patients with aggressive, difficult to treat disease. The goal of this project is to profile expression of Fc receptor across immune cell populations in AML patient bone marrow toward informing rational design of optimized antibodies for AML therapy.

Dennis Schaefer-Babajew (Nussenzweig Lab): Effects of Passive mAb Administration on Subsequent Adaptive Immune Responses to Cognate Antigen. Antibodies are thought to be the primary active compound responsible for the protective effects elicited by challenge with antigen, such as in vaccination or infection. Additionally, the clinical use of monoclonal antibodies (mAbs) has been thoroughly established as a pillar of modern medicine in recent years. In this study, we propose to comparatively assess different aspects of adaptive immunity following vaccination against SARS-CoV-2 in individuals who previously received a combination of two potently neutralizing SARS-CoV-2 antibodies, C135 and C144 (NCT04700163). Beyond its conceptual value in elucidating our understanding of basic humoral immunobiology, this work should also establish whether prior administration of monoclonal antibodies has any deleterious or advantageous effects for the recipient when faced with a secondary antigenic challenge, be it infection or vaccination

Pilots Projects Led by Faculty and Postdoctoral Fellows

Timothy Kenny (Birsoy Lab): Examining the Role of Mitochondrial Glutathione in Organismal Metabolism and Non-Alcoholic Steatohepatitis (NASH). Glutathione (GSH) is a small molecule thiol conserved throughout eukaryotic evolution. GSH is produced in the cytosol but abundantly present in other organelles such as the mitochondria. Our previous work identified SLC25A39 as the mitochondrial GSH transporter and demonstrated that loss of SLC25A39 specifically depletes mitochondrial GSH. Using a recently generated mouse model, we propose to exploit this finding to study the role of mitochondrial GSH in vivo in the context of normal physiology and metabolic disease.

Mascha Koenen (Cohen Lab):  Thermogenic Adipose Tissue as a Regulator of Bone Quality. Thermogenic adipose tissue has beneficial impacts on whole body metabolism in mice and humans. In contrast to white adipocytes that store excess energy, thermogenic adipocytes contribute to increased energy expenditure through uncoupled respiration. In this proposal, I will test the novel hypothesis that thermogenic adipocytes regulate bone metabolism in mice and humans through the following aims: (1) determine the impact of loss and gain of thermogenic adipocyte activity on bone remodeling in mice and (2) investigate changes in bone quality in humans with and without thermogenic adipose tissue. These studies will provide an entirely new understanding of the impact of thermogenic adipocytes on bone biology and have the potential to identify novel therapeutic targets for anabolic bone remodeling.

Sohail Tavazoie/Mei Wenbin (Tavazoie Lab):  Identification of Human Germline Variants that Modulate Cancer Progression. Cancer is a leading cause of death and a major public health burden in the developed world and many developing countries. One key challenge in cancer treatment is interpatient heterogeneity, where patients with the same subtype of cancer experience distinct clinical outcome. It has long been speculated that germline genetics is one of the main contributors to the inter-patient heterogeneity, but few efforts were dedicated to study it. Here I propose a systematic study to identify human germline variants that modulate cancer progression through computational analysis and experimental validation. Preliminary unbiased computational analyses have identified 18 known or novel common germline variants that associate with breast cancer or melanoma progression. This work can also provide new insights into hereditary factors’ contribution to a major human disease.

Ruisi Wang (Simon Lab):  The Discovery of Antibody Against DNAJB1-PRKACA in Fibrolamellar Hepatocellular Carcinoma. Fibrolamellar hepatocellular carcinoma (FLC) is an often-lethal liver cancer affecting primarily children and young adults. The disease presents with vague symptoms, and as a result, it is usually diagnosed at an advanced stage. Thus, even for those who undergo surgical resection, there remains a high rate of recurrence. There is a lack of both existing diagnostic tests and systemic therapies; hence FLC has an overall poor prognosis. We have found that the one recurrent alteration in the genome is a somatic deletion that is only in the tumor tissue of ~400kB that produces a chimeric transcript, DNAJB1, fused to PRKACA, expressed in all tumor samples but not in adjacent normal liver. We have also shown that the expression of this chimeric protein is sufficient to produce the disease. We can detect antibodies that recognize DNAJB1-PRKACA, but not either of the parental molecules, from the plasma of patients with FLC. We sort the PBMCs isolated from patients to collect B cells, which are secreting DNAJB1-PRKACA specific antibodies. We aim to screen, identify, sequence and express patient-derived antibodies against the chimeric fusion protein.

Zhaoyue Zhang (Friedman Lab):  Regulation of Feeding by Dietary Fat. Food intake and body weight are regulated by an array of hormonal and metabolic signals. The role of hormones has been confirmed by genetic and physiologic studies while the role of metabolic signals is suggested by the effect of dietary changes on weight. I now propose to study the mechanism of how these different dietary fats regulate feeding and metabolism by combining a set of biochemical, metabolomic and neurobiologic techniques. This study will have the potential to deepen our knowledge of how a ketogenic diet exerts its effect and potentially optimize it, as well as, revealing how it reduces feeding and improves metabolic regulation.