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Email UsTarget Inhibition and Silencing: "Hits to Lead" Advances in Clinical and Translational Research
In this initiative of the Harvard Catalyst Translational Innovator Program, in partnership with the ICCB-Longwood Screening Facility, the community was invited to develop proposals that apply the high-throughput laboratory automation, or small molecule or siRNA library screening capabilities of ICCB-Longwood to problems of clinical and translational importance as they pertain to human health. Applications were required to focus on human specimens or human disease in areas such as infectious disease or biodefense, therapeutic targets, emerging human disease pathways, gene knockdown and functional genomics, or target silencing and inhibition.
Funding Decisions were announced in December 2014
Sponsoring Program
Awardees
Principal Investigator: Donald Coen, PhD, Harvard Medical School
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes severe disease in immunocompromised individuals such as transplant and chemotherapy recipients and patients with HIV. HCMV is also a major cause of birth defects, with deafness and mental retardation frequent outcomes.
This proposal addressed the need for new anti-HCMV drugs by focusing on the HCMV nuclear egress complex (NEC) as a novel target for drug discovery.
Principal Investigator: Jeffrey D. Dvorin, MD, PhD, Boston Children’s Hospital
Human malaria is a leading cause of death and disease worldwide. The most severe forms of malaria result from infection by the Plasmodium falciparum parasite.
This project utilized the automated liquid handling facilities at ICCB-Longwood, where they performed a genetic screen for essential genes in P. falciparum. The long-term objective of this study was to identify novel targets for new antimalarial therapeutics.
Christopher A. French, MD, Brigham and Women’s Hospital
This projected proposed to develop a new drug to improve treatment of an incurable cancer, NUT midline carcinoma (NMC). NMC affects people of all ages with nearly zero survival.
Principal Investigator: Alfred Goldberg, PhD, Harvard Medical School
Tuberculosis remains one of the leading causes of death from infectious diseases worldwide. Mycobacterium tuberculosis (Mtb) has become increasingly resistant to available antibiotics.
The ATP-dependent serine protease complex (ClpXP1P2) is essential for growth and infectivity of Mtb and because similar enzymes are not present in the mammalian cytosol, they are attractive drug targets.
This project aimed to screen for inhibitors in the small molecule library at the ICCB-Longwood facility. This work may identify lead compounds for the development of novel treatments for tuberculosis.
Principal Investigator: Elizabeth Henske, MD, Brigham and Women’s Hospital
Lymphangioleiomyomatosis (LAM) is an often-fatal destructive lung disease of young, nonsmoking women. LAM cells carry mutations in the tuberous sclerosis complex (TSC) genes. This project will use results from a previous small molecule screen to identify molecular targets that selectively induce death in TSC2-deficient, patient-derived cells.
Principal Investigator: James E. Kirby, MD, Beth Israel Deaconess Medical Center
The abstract for this grant award is not available at the request of the Principal Investigator.
Principal Investigator: Ralph Scully, MB BS, PhD, Beth Israel Deaconess Medical Center
The repair of double strand breaks (DSBs) plays a crucial role in cancer predisposition and cancer therapy.
DSB repair entails two major pathways: homologous recombination (HR) and non-homologous end joining (NHEJ). Transient inhibition of DSB repair might be useful as a method for sensitizing tumors to radiotherapy (“radiosensitization”), allowing the dose of radiation to the patient to be minimized.
The goal of this project was to work with the ICCB-Longwood screening facility to conduct a high-throughput screen for small interfering RNAs (siRNA) that modulate NHEJ in human cells, with the aim of identifying new human NHEJ gene.
Principal Investigator: Priscilla Yang, PhD, Harvard Medical School
Dengue virus (DV) is the most widespread mosquito-borne viral disease affecting humans today. DV causes a broad spectrum of disease ranging from the asymptomatic to classical dengue fever and can progress to more severe and life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Efforts to develop antivirals targeting conventional viral polymerase and protease targets have also been unsuccessful.
This project proposes a one year high throughput screening effort to identify alternative scaffolds against these targets. Our long-term plan is to develop DV entry inhibitors that can be advanced as preclinical candidates.