Elucidating the role of secretory leukocyte protease inhibitor in autoimmune diabetes.
The Research Project:
Although many therapies targeting the adaptive immune system have been tested in patients to overcome their insulin dependence, medical research has encountered a very limited success to halt the onset or to reverse type 1 diabetes. There is an urgent need to develop innovative therapies that prevent T1D targeting the initiation of the autoimmune cascade. The discovery of very-early biomarkers, and potentially others, offers the opportunity to prevent the development of T1D by targeting the early events that initiate the diabetogenic cascade. Some years ago, we revealed the role of neutrophils in the initiation of autoimmune diabetes (Diana et al. Nat. Med. 2011), raising the possibility that neutrophils may be a relevant candidate for therapeutic interventions. A physiological regulator of neutrophil activity is the secretory leukocyte protease inhibitor (SLPI), an antimicrobial peptide constitutively secreted by most mucosal epithelial cells. SLPI is as an important anti-inflammatory molecule preventing harmful excessive response from neutrophils. Noteworthy we discovered that SLPI is expressed in human and mouse pancreatic islets prompting us to investigate whether SLPI could regulate the development of T1D and, at middle term, whether SLPI inducers could be used as attractive therapeutic tools against T1D.
Research keywords: Antimicrobial peptides, autoimmunity, mouse models, diabetes.
The applicant should be a highly motivated postdoctoral candidate with a PhD degree in Immunology and a high-quality track record. He/she should have a strong background in performing research in mouse immunology.
The Research Environment:
The research Unit is Institut Necker Enfants Malades (INEM), a biomedical research center aiming at fundamental discoveries with the potential of leading to therapeutic progress, focusing on incurable chronic diseases. Our faculty includes 19 teams with an international background and two departments: "Cell Biology (growth and signaling)" and "Immunology, Infectiology, and Hematology".
INEM shares a unique research campus with the IMAGINE institute and the Hôpital Necker-Enfants Malades, which, supported by state-of-the-art core facilities, together provide a rich and vibrant environment for basic research and translational innovation. PIs at INEM have first-rate expertise in immunology, basic physiology, cellular biology, and molecular biology. The INEM teams collaboratively address multiple facets of diseases.
Julien Diana, PhD
Institut Necker Enfants Malades - INEM - INSERM U1151/CNRS UMR8253 160,
rue de Vaugirard
75015 Paris, FRANCE
E-mail : firstname.lastname@example.org
To apply: The candidate should send a curriculum with a brief statement of research experience, technical expertise and interests, and one or two references to Julien Diana.
24 months. Salary 2000 €/month from the Juvenile Diabetes Research Foundation. Starting in September 2022.
Selected references from the PI:
-NKT cell-plasmacytoid dendritic cell cooperation via OX40 controls viral infection in a tissue-specific manner. Diana J, Griseri T, Lagaye S, Beaudoin L, Autrusseau E, Gautron AS, Tomkiewicz C, Herbelin A, Barouki R, von Herrath M, Dalod M, Lehuen A. Immunity 2009. (IF :24.2).
-Viral infection prevents diabetes by inducing regulatory T cells through NKT cell- plasmacytoid dendritic cell interplay. Diana J, Brezar V, Beaudoin L, Dalod M, Mellor A, Tafuri A, von Herrath M, Boitard C, Mallone R, and Lehuen A. J. Exp. Med. 2011. (IF :15.1).
-Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Diana J*, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, and Lehuen A. Nat. Med. 2013. (IF :22.5) (*: corresponding author).
-Macrophages and β-cells are responsible for CXCR2 -mediated neutrophil infiltration of the pancreas during autoimmune diabetes. Diana J* and Lehuen A. EMBO Mol. Med. 2014; (IF:9.4); (*: corresponding author).
-Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota. Sun J, Furio L, Mecheri R, van der Does A, Lundeberg E, Saveanu L, Chen Y, van Endert P, Agerberth B, and Diana J. Immunity 2015. (IF: 21.5).
-Lactose Induces Phenotypic and Functional Changes of Neutrophils and Macrophages to Alleviate Acute Pancreatitis in Mice. Li-Long Pan, Yuan-Yuan Deng, Chengfei Wu, Jiahong Li, Wenying Niu, Madhav Bhatia, Birgitta Agerberth, Gudmundur H. Gudmundsson, Julien Diana†, Jia Sun†. Front. Immunol. 2018. (IF: 6.4). (†: authors contribute equally).
-Gut Microbiota-Stimulated Innate Lymphoid Cells Support β-Defensin 14 Expression in Pancreatic Endocrine Cells, Preventing Autoimmune Diabetes. Miani M, Le Naour J, Enée E, Verma SC, Straube M, Emond P, Ryffel B, van Endert P, Sokol H, Diana J. Cell Metab. 2018. (IF: 20.5).
-The Dual Role of Antimicrobial Peptides in Autoimmunity. Liang W, Diana J. Front Immunol. 2020. (IF:4.5).
-Gut microbiota-CRAMP axis shapes intestinal barrier function and immune responses in dietary gluten-induced enteropathy. Ren Z, Pan LL, Huang Y, Chen H, Liu Y, Liu H, Tu X, Liu Y, Li B, Dong X, Pan X, Li H, Fu YV, Agerberth B, Diana J†, Sun J†. EMBO Mol. Med. 2021 (IF:10.2) (†: authors contribute equally).
-Intestinal Cathelicidin Antimicrobial Peptide Shapes a Protective Neonatal Gut Microbiota against Pancreatic Autoimmunity. Liang W, Enée E, Andre-Vallee C, Falcone M, Sun J, Diana J. Gastroenterology 2022 (IF:22.6).