Martin Dorf, PhD
Department of Pathology, Harvard Medical School
Molecular signaling in inflammation: TNF; cytokine; autoimmune disease; T-cell
Investigate the biochemical signaling perturbations elicited by the pro-inflammatory cytokine TNF that serve to modulate the activation of NF-кB, with a focus on TNF receptor-associated factor 2 (TRAF2), an intracellular protein that forms a multimeric complex with the TNF receptor and
Dissect the TNF-activated signaling pathways in order to design more specific treatments for diseases such as cancer and autoimmune disorders, including rheumatoid arthritis, Crohn's disease, and psoriasis
Dysregulation of the inflammatory signaling cascade that is set in motion by TNF is thought to contribute to a host of pathological conditions. Current anti-TNF treatments, such as antibodies (for example, Remicade) and soluble decoy fusion receptors (for example, Enbrel), do not discriminate between the two TNF receptors (TNF-R1 and TNF-R2). Yet, the TNF-R1 expression is ubiquitous while the TNF-R2 expression is primarily restricted to immune cells. Also, signaling through the two receptors may elicit different cellular effects. Because the roles of the two TNF receptors are not entirely clear, it is possible that new therapeutics can be developed that are more selective for various disorders and may be more efficacious in certain contexts. This research represents an attractive opportunity for a corporate partner to collaborate on medically-relevant studies that ultimately may lead to improved therapeutics.
Current Research Interests
Dr. Dorf's current research includes:
Study of TRAF2 phosphorylation induced by TNF:
Explore the effects of TRAF2-Thr117 phosphorylation and its dephosphorylation on IKK (IkaapaB kinase, the kinase responsible for inactivating the NF-kappaB inhibitor IkappaB) activity as well as on polyubiquitination of TRAF2
Study of the regulation of TRAF2-Thr117 phosphorylation and dephosphorylation
Investigate the consequences of TRAF2-Thr117 phosphorylation on JNK and NF-kappaB activation
Study of the cellular mechanisms that promote and maintain the MEKK3-TAK1 complex, the mechanism of complex dissociation by TAB1, and how proinflammatory signals from the TNF receptor govern TAB1 regulation of NF-кB activation.
Discrimination of the pro-inflammatory signaling pathways from the two TNF receptors, TNFR1 and TNFR2, as well as their roles in disease. For example, TNFR1 is on almost every cell type in the body and has growth promoting effects on certain tumors, such as gliomas, head/neck tumors, and leukemias.
Study of the approaches for selectively muting a subset of IKK-mediated downstream responses.
Investigation into the specific activities of effector T-lymphocyte clones that contribute to the pathophysiology of certain autoimmune diseases and the mediators that regulate these functions.
Dr. Dorf’s laboratory has studied the intracellular biochemical signaling cascades triggered by the engagement of cell surface receptors with inflammatory cytokines, such as the tumor necrosis factor α (TNF). The lab has also investigated the role of T-lymphocytes and their repertoire of secreted cytokines in the inflammatory process. One of the key intracellular targets activated by TNF is NF-кB, a transcription factor that is sequestered in the cytoplasm in its inactive state. The lab has uncovered important regulatory features relating to kinases and phosphatases that govern the release of NF-кB from its cytoplasmic molecular constraints and subsequent translocation to the nucleus, where it activates the transcription of numerous genes. In the most recent studies, the lab has demonstrated that TAK1 and MEKK3, which participate in NF-кB activation, form a complex within cells that display only basal levels of NF-кB activation. This protein complex functions to prevent MEKK3 phosphorylation and thus maintain NF-кB “shackled” to its inhibitors in the cytoplasm. The lab’s data also revealed that this protein complex is regulated by the TAK1-binding protein TAB1, which responds to cytokine-mediated signals by promoting autophosphorylation of TAK1 and dissolution of the TAK1-MEKK complex, resulting in activation of NF-кB.
In addition, the lab has studied the role of TH1 and TH17 lymphocytes in the etiology of experimental autoimmune encephalomyelitis (EAE) and has discovered compensatory regulatory mechanisms that trigger the inflammatory response in EAE. The lab used cloned T cells to dissect the distinct subtypes of effector lymphocytes that induce EAE, their cytokine profiles, and relevant transcription factors.