Four DF/HCC members receive NIH Director’s New Innovator Award
Despite current constraints, the NIH continues to award funding to a number of DF/HCC research initiatives. Recently, these awards included four NIH Director’s New Innovator Awards, which provide support to promising investigators who have yet to become PIs on an R01 or equivalent grant, or leaders of a P01 or center grant peer-reviewed project. The concept behind this new funding mechanism is that these individuals often have exceptionally innovative research ideas, but lack the required preliminary data to compete successfully in the traditional peer review system at this stage in their career.
In total, the NIH awarded 29 Innovator Awards this year. Each awardee will receive approximately $2.5m in total costs over five years. The four DF/HCC recipients and their projects are:
Defining Melanoma Therapeutic Avenues by Integrative Functional Genomics
Levi Garraway, MD, PhD (DFCI)
Project Abstract: Garraway will apply pooled RNAi and small molecule microarray screening sequentially to a panel of genetically characterized and patient-derived melanoma cell lines. We will assemble a lentiviral library targeting all expressed genes located within the portion of the genome that is amplified in melanoma, and perform pooled RNAi screening across a panel of 20 melanoma lines representative of the most prevalent melanoma genomic alterations. We will validate the most promising target genes using a series of cell survival assays in vitro (in arrayed RNAi format) and tumor formation assays in vivo (using shRNA ‘mini-pools'), and identify candidate ligands that bind the top target (onco)protein candidates by performing small-molecule microarray screens using epitope-tagged protein constructs. If successful, this project should elaborate a spectrum of target proteins and potential lead compounds linked to common genetic changes in melanoma. Moreover, these efforts should inform a “platformizable” integrated approach applicable to all cancers for which tractable in vitro models exist.
Revealing pathogen-sensing pathways using RNAi libraries
Nir Hacohen, PhD (MGH)
Project Abstract: Hacohen will apply a genome-wide lentiviral RNAi library to dissect innate immune pathways in mammals. We will use a novel experimental strategy to explore an elaborate and ancient sensory system that detects pathogen-derived nucleic acids. Our two objectives are to identify a set of unknown DNA sensors and their pathways, and to understand how DNA and RNA sensors avoid being inappropriately activated by host DNA and RNA. We will identify genes and proteins in the unknown DNA-sensing pathways and explore the mechanisms that inhibit the sensing of self nucleic acids. By understanding this detection system in depth, we will gain insight into the perpetual struggle between parasitic elements and their hosts, and the risks of autoimmunity in response to the host's own nucleic acids. In addition, the results of the studies will help in the rational development of vaccines using adjuvants that target nucleic acid sensors.
Reprogramming of somatic cells by defined factors
Konrad Hochedlinger, MSc, PhD (MGH)
Project Abstract: Hochedlinger has generated induced pluripotent stem (iPS) cells directly from fibroblasts by retroviral overexpression of the transcription factors Oct4, Sox2, c-myc and Klf4. In contrast to the previously reported iPS cells, our iPS cells were indistinguishable from ES cells in their epigenetic state and developmental potential. Several crucial questions were raised by these findings; (i) what is the sequence of molecular changes that accompany nuclear reprogramming, (ii) what is the kinetics of reprogramming and does it require cell division, (iii) are different cell types at different differentiation stages equally amenable to reprogramming, and (iv) can human cells be reprogrammed into iPS cells? The current limitations to solve these questions are the low efficiency of direct reprogramming and the inability to follow reprogramming in real time. We will tackle these questions by generating “reprogrammable mice” in which every single cell can be reversibly induced to express the four factors at levels necessary for reprogramming, and by attempting to reprogram human cells. We will determine the robustness and kinetics of reprogramming, the hierarchy of transcriptional and epigenetic changes that accompany nuclear reprogramming, the responsiveness of different cell types to the four factors, and the feasibility of human reprogramming.
MicroRNA Biogenesis and the Cancer Proteome
Mark Johnson, MD, PhD (BWH)
Project Abstract: Johnson propses a new strategy to identify the mechanisms by which defects in microRNA biogenesis decrease cancer survivorship. This approach involves the integration of genome-scale high throughput quantitative mass spectrometry analysis of the cancer proteome with genome-wide microRNA, mRNA and DNA analyses of human brain tumors (glioblastomas) that have intact or defective microRNA biogenesis. This innovative and ambitious project will integrate mass spectrometry proteomics, genomics and clinical variables to comprehensively identify the mechanisms underlying the decreased cancer survivorship associated with dysregulated microRNAbiogenesis.
