Descripción del proyecto
La compleja red intestinal de linfocitos en la enfermedad inflamatoria intestinal
La enfermedad inflamatoria intestinal (EII) representa un grupo de trastornos intestinales que provocan la inflamación prolongada del tracto digestivo. El descubrimiento y la caracterización recientes de las células linfoides innatas revelaron que estas desempeñan un papel importante en la inmunidad de la mucosa que se suma al de los linfocitos T adaptativos específicos. El proyecto financiado con fondos europeos GUT-SEQ aprovecha esta investigación para determinar la complementariedad y redundancia de los dos sistemas linfocíticos para entender mejor las enfermedades inflamatorias y desarrollar nuevos tratamientos. El proyecto empleará la secuenciación de ARN unicelular para llevar a cabo una disección molecular exhaustiva de los compartimentos linfocitarios del intestino humano en la EII utilizando una toma única de muestras de pacientes. Los investigadores determinarán los mecanismos de enfermedades graves, identificarán nuevas subpoblaciones de linfocitos adaptativos e innatos que se encuentran en los tejidos y guardan relación con la inflamación, revelarán nuevas dianas terapéuticas y cómo estas se pueden utilizar para tratamientos personalizados.
Objetivo
Inflammatory bowel disease (IBD) constitutes an increasing global health burden, yet effective treatments are lacking. Hampering rationale treatment strategies, the human intestinal immune system remains largely unexplored. I have made seminal contributions to the discovery and characterization of innate lymphoid cells (ILCs) (Nat Immunol 2011, 2013 and 2016, Immunity 2012), revealing that in addition to antigen-specific adaptive T cells, innate equivalents play important roles in mucosal immunity. Determining the complementarity and redundancy of these two lymphocyte systems, acting in concert, is important for our understanding of inflammatory diseases and the development of novel therapies. For this proposal, I am in the beneficial position of having access to unique patient samples as well as established methods for single-cell RNA-sequencing to perform an ambitious and comprehensive molecular dissection of the human intestinal lymphocyte compartments in IBD. With this approach, I will determine parallels between known, and identify novel, subsets of tissue-resident, inflammation-associated, innate and adaptive lymphocytes. Building on this unprecedented molecular characterization, we will take on some of the most pressing clinical problems in IBD by performing longitudinal assessments of intestinal lymphocytes from IBD patients on conventional and biological treatments. As only a fraction of patients respond to treatment, this approach provides a golden opportunity to unveil immunological signatures of treatment response and “drug-induced transformation” of inflammation in non-responders. Furthermore, we will unfold critical disease mechanisms and reveal novel therapy targets and how they can be used to personalize treatment. In summary, my ambitious, yet feasible, proposal combines state-of-the-art technology with access to unique patient materials. My studies are likely to advance our understanding of the complex intestinal lymphocyte network in IBD.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
17177 Stockholm
Suecia