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  • Intestinal Chloride Secretion

    Principal Investigator:
    Ming-Tseh Lin, M.D., Ph.D.
    Medicine

    Intestinal chloride secretion is stimulated during diarrhea. Cholera toxin is secreted by bacte...rium Vibrio cholera and is responsible for the watery diarrhea after cholera infection. Mechanistically, cholera toxin increases intracellular cyclic AMP, which subsequently activates protein kinase A and the cystic fibrosis transmembrane regulator chloride channel (CFTR).

    However, we recently identified an intestinal cAMP-Ca cross-talk signaling pathway that is initiated by elevation of intracellular cAMP and subsequently elevates intracellular Ca concentrations through the exchange protein activated by cAMP (Epac). This observation suggests that both CFTR and calcium-activated chloride channels are targets of elevated intracellular cAMP signaling molecule.

    Therefore, we are studying the role of calcium-activated Cl channels in intestinal chloride secretion under physiological conditions and during diarrhea. We are also determining whether the recently identified transmembrane protein 16 family of proteins, which are calcium-activated chloride channels, is also involved in intestinal chloride secretion in addition to the well characterized CFTR channel.

    Increased understanding of regulation of intestinal Cl secretion provides the necessary background information for the development of therapeutic drugs for the treatment of diarrhea, constipation and cystic fibrosis. The discovery that calcium-activated chloride channels are involved in intestinal chloride secretion provides additional targets for anti-diarrhea drug development.
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    Research Areas: gastroenterology, diarrhea
  • Jodi Segal Lab

    Principal Investigator:
    Jodi Segal, M.D., M.P.H.
    Medicine

    Research in the Jodi Segal Lab focuses on developing methodologies to use observational data to... understand the use of new drugs, particularly drugs for treating diabetes, blood disorders and osteoporosis. We apply advanced methods for evidence-based review and meta-analysis, and—in collaboration with Johns Hopkins biostatisticians—we have developed new methodologies for observational research (using propensity scores to adjust for covariates that change over time) and methods to account for competing risks and heterogeneity of treatment effects in analyses. view more

    Research Areas: blood disorders, osteoporosis, diabetes, drugs, evidence-based medicine
  • John Schroeder Lab

    Principal Investigator:
    John Schroeder, Ph.D.
    Medicine

    The John Schroeder Lab focuses on understanding the role human basophils and mast cells play in... allergic reactions, as it relates not only to their secretion of potent inflammatory mediators (e.g., histamine and leukotriene C4) but also to their production of pro-inflammatory cytokines. We have long utilized human cells rather than cell lines in order to address the parameters, signal transduction and pharmacological aspects underlying clinically relevant basophil and mast cell responses. As a result, the lab has established protocols for rapidly isolating large numbers of basophils at high purity from human blood and for growing culture-derived mast cells/basophils from human progenitor cells. A variety of assays and techniques are also in place for concurrently detecting cytokines and mediators following a wide range of stimuli. These have facilitated the in vitro testing of numerous anti-allergic drugs for inhibitory activity on basophil and mast cell activation. The lab also studies counter-regulation between the IgE and innate immune receptors on human immature dendritic cell subtypes. view more

    Research Areas: cell biology, allergies, inflammation
  • John T. Isaacs Laboratory

    Lab Website
    Principal Investigator:
    John Isaacs, Ph.D.
    Oncology

    While there has been an explosion of knowledge about human carcinogenesis over the last 2 decad...es, unfortunately, this has not translated into the development of effective therapies for either preventing or treating the common human cancers. The goal of the Isaacs’ lab is to change this situation by translating theory into therapy for solid malignancies, particularly Prostate cancer. Presently, a series of drugs discovered in the Isaacs’ lab are undergoing clinical trials in patients with metastatic cancer.

    The ongoing drug discovery in the lab continues to focus upon developing agents to eliminate the cancer initiating stem cells within metastatic sites of cancer. To do this, a variety of bacterial and natural product toxins are being chemically modified to produce “prodrugs” whose cytotoxicity is selectively activated by proteases produced in high levels only by cancer cells or tumor associated blood vessel cells. In this way, these prodrugs can be given systemically to metastatic patients without un-acceptable toxicity to the host while being selectively activated to potent killing molecules within metastatic sites of cancer.

    Such a “Trojan Horse” approach is also being developed using allogeneic bone marrow derived Mesenchymal Stem cells which are genetically engineered to secrete “prodrugs” so that when they are infused into the patient, they selectively “home” to sites of cancers where the appropriate enzymatic activity is present to liberate the killing toxin sterilizing the cancer “neighborhood”.
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    Research Areas: anti-cancer drugs, stem cell biology
  • Jun O. Liu Laboratory

    Lab Website

    The Jun O. Liu Laboratory tests small molecules to see if they react in our bodies to find pote...ntial drugs to treat disease. We employ high-throughput screening to identify modulators of various cellular processes and pathways that have been implicated in human diseases from cancer to autoimmune diseases. Once biologically active inhibitors are identified, they will serve both as probes of the biological processes of interest and as leads for the development of new drugs for treating human diseases. Among the biological processes of interest are cancer cell growth and apoptosis, angiogenesis, calcium-dependent signaling pathways, eukaryotic transcription and translation. view more

    Research Areas: cancer, autoimmune, eukaryotic cells, drugs, cellular signaling, pharmacology, calcium-dependent signaling pathways, molecular biology, angiogenesis
  • Kelly E. Dooley Laboratory

    Lab Website

    Research focuses on clinical pharmacology of new anti-tuberculosis regimens with an emphasis on...: (1) Phase I clinical trials of new or existing anti-TB drugs including dose escalation trials and studies of drug-drug interactions between anti-TB agents and antiretrovirals to treat HIV; (2) Use of PK/PD analysis and modelling in Phase II tuberculosis clinical treatment trials to determine concentration-effect relationships that will allow for optimization of dosing; and (3) Evaluation of TB and HIV drug concentrations in special populations, such as pregnant women and children; (4) Evaluation of treatment-shortening regimens for drug-sensitive TB and investigational regimens for treatment of multidrug-resistant TB; and (5) Translational work involving novel animal models of cavitary pulmonary TB disease to understand drug distribution in diseased lung. view more

    Research Areas: anti-infective drugs, antiretroviral therapies, tuberculosis and HIV treatments, HIV, lung disease, pharmacology, tuberculosis
  • Michael Kornberg Lab

    Lab Website

    Our laboratory conducts basic and translational research aimed at better understanding the path...ogenesis of multiple sclerosis (MS) and the role of the immune system in CNS disease, particularly the processes that drive progressive disability such as neurodegeneration and remyelination failure. We currently have three parallel research programs: 1. Metabolism as a modulator of MS: We are studying how basic metabolic pathways regulate the immune system and how these pathways might be exploited to protect neurons and myelin-forming oligodendrocytes from injury. 2. Identifying pathways by which nitric oxide (NO) and other free radicals cause neuronal and axonal damage. Our lab is identifying specific signaling pathways initiated by NO and other free radicals that can be targeted by drugs to produce neuroprotection. 3. Modulating the innate immune system in MS: In collaboration with others at Johns Hopkins, we are studying ways to enhance the reparative functions of microglia while preventing maladaptive responses. This work has identified bryostatin-1 as a potential drug that may be re-purposed for this task. view more

    Research Areas: multiple sclerosis
  • Namandje N. Bumpus Lab

    Lab Website
    Principal Investigator:
    Namandje Bumpus, Ph.D.
    Medicine

    The Bumpus Laboratory uses mass spectrometry and molecular pharmacology-based approaches to stu...dy the biotransformation of clinically used drugs by the cytochromes P450s. Specifically, we are studying ways to define a role for cytochrome P450-dependent metabolites in the drug-induced acute liver failure that is associated with certain antiviral drugs used to treat HIV and hepatitis C. Our long-term goal is to gain information that can be used to develop therapies that are devoid of toxic events by preventing the formation of a toxic metabolite or by developing strategies for preventing toxicity using concomitant therapy. view more

    Research Areas: antiviral therapy, drug metabolism, mass spectrometry, HIV, drugs, cellular signaling, cytochromes P450, pharmacology, molecular pharmacology, hepatitis C, metabolomics
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