Kashkar, Hamid - B 06
Role of IAPs in TNF-induced vasculature alteration and their therapeutic value in inflammatory diseases
Prof. Dr. Hamid Kashkar
Institute for Molecular Immunology | CECAD Research Center
CMMC - PI - B 06
Head - CMMC Cell Sorting Facility
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Institute for Molecular Immunology | CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne
Introduction
TNF is an inflammatory cytokine that has pleiotropic effects on various tissues. Its central role in inflammation has been lately demonstrated by the efficacy of anti-TNF antibodies in controlling inflammatory diseases.
Vascular endothelium represents one of the major targets of TNF which emits diverse responses when exposed to inflammatory conditions. Disease-associated pathogenic vascularization or vascular destruction often occurs in response to excessive TNF. The underlying molecular mechanisms of such diverse vascular responses to TNF have not been yet elucidated. Here we will explore the molecular mechanism of pleiotropic EC responses to TNF and further aim to develop a novel therapeutic concept in order to normalize vessel functions under inflammatory condition. We will in particular focus on inhibitor of apoptosis proteins (IAPs) as key regulating diverge cellular responses to TNF.
We will strongly benefit from newly established transgenic mice in our laboratory which harbor EC-specific alteration of IAPs and will utilize experimental disease model systems addressing the function of TNF/IAPs in vessel integrity/function in wound healing and tumor growth. We will implement novel drugs specifically targeting IAPs and their two major downstream targets, RIPK1 and NIK, under disease condition. The data obtained will significantly increase our knowledge about the vascular responses to inflammatory disease conditions and will provide important impetus for developing novel therapeutic protocols for inflammatory disorders.
Clinical Relevance
Inflammatory diseases affect approximately 7.6–9.4% of the world population. The majority of these diseases involves vascular endothelium leading to multi-organ involvement. Anti-TNF therapy can efficiently reduce tissue damage and improve vascular function. This project aims to exploit the recent in-depth molecular knowledge on TNF signaling and evaluate emerging novel compounds which interfere with TNF-signaling as new therapeutic options for inflammatory disorder.
Approach
- Transgenic mouse model
- in vitro angiogenesis assay
- therapeutic evaluation of new compound
Affiliations
- CECAD Cologne
- Institute for Molecular Immunology
- CRC 1403: Cell Death in Immunity, Inflammation and Disease
- CRC 1218: Mitochondrial regulation of cellular function
- CRC 1530: Aufklärung und Targeting pathogener Mechanismen bei B-Zell-Neoplasien
- CRC 1607: Towards immunomodulatory and anti(lymph)angiogenic therapies for age-related blinding eye diseases
Publications generated during 1/2023-12/2025 with CMMC affiliation
2024 (up to June)
- Injarabian L, Willenborg S, Welcker D, Sanin DE, Pasparakis M, Kashkar H, and Eming SA (2024). FADD- and RIPK3-Mediated Cell Death Ensures Clearance of Ly6C(high) Wound Macrophages from Damaged Tissue. J Invest Dermatol144, 152-164 e157. doi:10.1016/j.jid.2023.06.203.
2023
- Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, and Cursiefen C (2023). The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res 96, 101157. doi:10.1016/j.preteyeres.2022.101157.
- Injarabian L, Willenborg S, Welcker D, Sanin DE, Pasparakis M, Kashkar H, and Eming SA (2024). FADD- and RIPK3-Mediated Cell Death Ensures Clearance of Ly6C(high) Wound Macrophages from Damaged Tissue. J Invest Dermatol 144, 152-164 e157. doi:10.1016/j.jid.2023.06.203.
- Kruse B, Buzzai AC, Shridhar N, Braun AD, Gellert S, Knauth K, Pozniak J, Peters J, Dittmann P, Mengoni M, van der Sluis TC, Hohn S, Antoranz A, Krone A, Fu Y, Yu D, Essand M, Geffers R, Mougiakakos D, Kahlfuss S, Kashkar H, Gaffal E, Bosisio FM, Bechter O, Rambow F, Marine JC, Kastenmuller W, Muller AJ, and Tuting T (2023). CD4(+) T cell-induced inflammatory cell death controls immune-evasive tumours. Nature 618, 1033-1040. doi:10.1038/s41586-023-06199-x.
- Maekawa T, Kashkar H, and Coll NS (2023). Dying in self-defence: a comparative overview of immunogenic cell death signalling in animals and plants. Cell Death Differ 30, 258-268. doi:10.1038/s41418-022-01060-6.
- Schiffmann LM, de Groot E, Albert MC, Quaas A, Pinto Dos Santos D, Babic B, Fuchs HF, Walczak H, Chon SH, Ruurda JP, Kashkar H, Bruns CJ, Schroder W, and van Hillegersberg R (2023). Laparoscopic ischemic conditioning of the stomach prior to esophagectomy induces gastric neo-angiogenesis. Eur J Surg Oncol 49, 107096. doi:10.1016/j.ejso.2023.107096.
- Schorn F, Werthenbach JP, Hoffmann M, Daoud M, Stachelscheid J, Schiffmann LM, Hildebrandt X, Lyu SI, Peltzer N, Quaas A, Vucic D, Silke J, Pasparakis M, and Kashkar H (2023). cIAPs control RIPK1 kinase activity-dependent and -independent cell death and tissue inflammation. EMBO J 42, e113614. doi:10.15252/embj.2023113614.