Center for Clinical and Translational Science

The Rockefeller University Center for Clinical and Translational Science (CCTS) and the Center for Basic and Translational Research on Disorders of the Digestive System (CDDS) awarded 38 pilot projects this year (20 CCTS and 18 CDDS). Ten recipients are CCTS Clinical Scholars and 2 are to Rockefeller Early Phase Physician Scientists (REPPS). A total of 47 applications were submitted, representing the highest number received to date. CCTS committed $392,000, CDDS committed $312,500, and $25,000 was provided by the Katerina and Andreas C. Dracopoulos Family Science and Society Initiative at The Rockefeller University, for a total commitment of $729,500. This brings the grand total of pilot project funding to $2,014,434 since this program was begun under the initial CTSA grant in 2006.

Pilots Projects Led by CCTS Clinical Scholars
1. Nathalie Burg, MD (Coller Lab): Proposal to discover and produce antibodies to latent transforming growth factor- â1 to elucidate mechanisms and improve the therapy of Systemic Sclerosis. This project will test the hypothesis that autoantibodies and/or enhanced shear stress in SSc microvasculature facilitates thiol-disulfide exchange and ongoing TGF-â1 activation. It will also provide insights into the mechanism of shear-induced TGF-â1 activation by developing mAbs that inhibit the activation and by mutating the CXXC motifs in LTBP-1, which are candidates for mediating thiol-disulfide exchange.

2. Louis Cohen, MD (Brady Lab): Metagenomic analysis of bacterial natural products and their role in the intestinal microbiome. This project will establish an in-vitro infection system based on hepatocyte-like inducible pluripotent stem cells (iHLCs), which have been previously shown to support hepatitis C virus infection. Those cells will be infected with either a pseudo typed virus expressing a reporter gene or by a wild-type virus derived from HBV producing cell line or from infected patients’ sera. The potential to dissect the differentiation stage at which the iHLCs become permissive to HBV infection, and the ability to generate iHLCs from stem cells of individuals harboring different genetic backgrounds will enable us to address key questions such as host factors essential for HBV infection and the importance of certain genetic backgrounds in directing the natural history of HBV infection.

3. Thalia Parazi, MD, PhD (Tuschl Lab): Development of multicolor fluorescence RNA in situ-hybridization assays for breast cancer diagnosis and prognosis. This project will to develop a multicolor fluorescence RNA in situ hybridization (ISH) approach, by which gene and non-coding RNA (ncRNA) expression can be visualized at single-cell resolution along with histological parameters to enhance the accuracy of breast cancer diagnosis for three known breast cancer markers; at the same time we aim to identify ncRNAs that may serve as reference controls or comprise diagnostic and prognostic markers.

4. Daniel Gareau, PhD (Krueger Lab): The Melanoma Advanced Imaging Dermatoscope. This project will creat the hardware and software to expand the spectral range of the mAID from the UV (300nm) to the IR (1600nm). The overall goal is to better identify spectral ranges of diagnostic value toward a comprehensive, automated imaging system as a clinical and research tool. Re-engineering the currently used dermatoscope from a conventional red/green/blue (RGB) camera, to one that images pigmented lesions across a wide spectral range beyond RGB, we would like to create an overall package that is relatively inexpensive and could be adopted in general dermatology practice.

5. Sharon Karmon, MD (Ho/Markowitz Lab): Mediators of immune activation and senescence in HIV-1 infected subjects. This project will explore the effects of starting cART during acute, early or chronic infection on markers of inflammation and immune senescence, as preliminary data has supported the hypothesis that very early use of antiretroviral therapy correlates with normalization of markers.

6. Florian Klein, MD (Nussenzweig Lab): Improvement of HIV-therapy by a combination of anti-retroviral medication and broad neutralizing antibodies in humanized mice. This project will investigate the potential improvement in HIV-therapy by combining classical/anti-retroviral therapy with the new antibody treatment modality in HIV-1-infected humanized-mice.

7. Xiao-Fei King, MD, PhD (Cassanova Lab): Genetic and immunological dissection of the pathogenesis of chronic mucocutaneous disease in patients with Down Syndrome. Down syndrome (DS) patients may have enhanced responses to interferons (IFNs) due to an extra chromosome 21, and may also suffer from an impaired immunity mediated by IL-17 T cells, which could explain the fungal infections and provide a new avenue for treatment. This project will investigate DS patients’ IFN responses and IL-17 immunity.

8. Ana Pereria, MD (McEwen Lab): Sleep Disordered Breathing and Glutamate-Induced Excitotoxicity in the Human Hippocampus as a Risk for Alzheimer’s disease. This project will study potential mechanisms through which Sleep-Disordered Breathing (SDB) may increase the risk of Alzheimer’s Disease (AD) by investigating the phenomenon of glutamate-mediated excitotoxicity and with measures of the pathological hallmarkers of AD, hyper phosphorylated tau and Aâ42.

9. Uri Sela, MD, PhD (Fischetti Lab): A novel approach to induce a protective immune response to a vaccine against Staphylococcus aureus. This project will induce T cell immunity by using a novel approach of dendritic cell (DC) targeting that was developed here at the Rockefeller University by the Ralph Steinman laboratory and is currently in clinical trials for an HIV vaccine. The novel vaccine approach in this pilot project will be tested for its protective capacity in a mouse model of S. aureus infection.

10. Amir Shlomai, MD,PhD (Rice Lab): Identifying essential host factors in hepatitis B virus life cycle by modeling infection in hepatocyte-like inducible pluripotent stem cells (iHLCs). This project will establish an in-vitro infection system based on hepatocyte-like inducible pluripotent stem cells (iHLCs), which have been previously shown to support hepatitis C virus infection. Those cells will be infected with either a pseudo typed virus expressing a reporter gene or by a wild-type virus derived from HBV producing cell line or from infected patients’ sera. The potential to dissect the differentiation stage at which the iHLCs become permissive to HBV infection, and the ability to generate iHLCs from stem cells of individuals harboring different genetic backgrounds will enable us to address key questions such as host factors essential for HBV infection and the importance of certain genetic backgrounds in directing the natural history of HBV infection.

Pilots Projects Led by REPPS

1. Jennifer Belasco, MD (Krueger Lab): Characterization of Inflammatory Pathways in Psoriatic Arthritis. Preliminary data shows that while the skin disease of psoriatic arthritis (PsA) is histologically similar to the skin disease of psoriasis vulgaris (PsV), the specific immune activation in the PsV lesional skin may be different than the PsA lesional skin. In this study, the gene expression patterns of lesional and non-lesional skin biopsies from subjects with PsA and PsV will be examined by gene array analysis and the connection between skin and joint symptoms will be further explored.

2. Manish Ponda, MD (Breslow Lab): The Effect of Oral Vitamin D vs. Ultraviolet Light on Cholesterol. A randomized, placebo-controlled trial was conducted to test the effect of oral vitamin D repletion on cholesterol. Oral vitamin D therapy failed to improve the lipid profile, and thus did not translate into the inferred benefit derived from epidemiologic studies. A plausible explanation for the uncoupling of epidemiologic and intervention-based data for vitamin D therapy and cholesterol may be due to the route of vitamin D administration. Therefore, we propose testing the effect of oral, exogenous vitamin D as compared to ultraviolet light-induced, endogenous vitamin D on the lipid profile.