INTERNAL MORPHOGENESIS AND HOMEOSTASIS

Our main scientific interest is the understanding of intestinal morphogenesis and cellular polarity during morphogenesis, homeostasis, and regeneration, as well as their implications in human diseases, such as cancer, inflammation and intestinal bowel diseases (IBD). Our research is based model systems such as organoids. Moreover, with this system, we are obtaining essential information about the molecular mechanisms that regulate epithelial morphogenesis. However, this model cannot reconstitute the complexity of the architecture given in vivo, which includes different cell types, dynamic remodeling, and tissue homeostasis. For this reason, the use of in vivo systems should serve to validate and better characterize the phenotypes observed in vitro. We used the zebrafish and mouse intestine as models systems to elucidate epithelial morphogenesis and intestinal homeostasis.

We are focused on the analysis of genes that regulate epithelial polarity during morphogenesis, and intestinal homeostasis, and particularly those controlling the following processes: Signaling, membrane trafficking, mechanical forces, and metabolic remodeling.

Group leader

Fernando Martín Belmonte

fmartin(ELIMINAR)@cbm.uam.es

Principal Investigator

  • Nuria Martínez Martín

Collaborators

  • Tatiana Alfonso Pérez
  • Gonzalo Herranz Gómez
  • Marta Iborra Pernichi
  • Gabriel Baonza Martínez
  • Tamara González Martínez
  • María Velasco de la Esperanza
  • Jonathan Ruiz García
  • Alejandra Isabel Ramos Manzano
Imagen equipo

Group leader

Fernando Martín Belmonte

fmartin(ELIMINAR)@cbm.uam.es

Principal Investigator

  • Nuria Martínez Martín

Collaborators

  • Tatiana Alfonso Pérez
  • Gonzalo Herranz Gómez
  • Marta Iborra Pernichi
  • Gabriel Baonza Martínez
  • Tamara González Martínez
  • María Velasco de la Esperanza
  • Jonathan Ruiz García
  • Alejandra Isabel Ramos Manzano

STRATEGIC OBJECTIVES 

· Previous studies have shown that control of cellular mechanics and mitotic spindle orientation are essential for adult organs and cancer development. We will address the mechanistic response of intestinal cells in target one and the orientation of the mitotic spindle in target two, which could yield key insights for CRC treatment.

· In recent years, our laboratory has developed and patented new three-dimensional (3D) micropatterned organotypic systems to model epithelial polarity and tubulogenesis in a robust and systematic way. Our projects use these "organ-on-a-chip" systems to grow human intestinal organoids in micropatterns. We take advantage of this organoid model to analyze the biochemical and biomechanical properties of epithelial organoids during intestinal development and address their impact on cancer development and progression.

· Protein absorption in neonates depends on intracellular digestion by LREs in the ileum and is essential during the early postnatal stages. Our previous work characterized the basic properties of these cells in nutrient absorption and nutrition (Herranz et al. in preparation). In the coming years we will continue to deepen our understanding of these intestinal cells and their relationship to autophagy, cell metabolism, and paracellular communication, all of which are essential for intestinal development and homeostasis, and their related conditions such as CRC.

· We will explore the use of the high absorption capacity of LREs to facilitate the entry of nanocarriers orally. Oral administration of biological drugs, including peptides, monoclonal antibodies, and nucleic acids, represents a very interesting drug delivery mechanism, both for patients and industry. This proposal will provide new approaches for the administration of biological drugs through biological barriers such as the intestinal tract. Many laboratories around the world are focused on improving nanotechnology to design new nanocarriers to deliver these biologic drugs. Instead, we are focusing on a completely new and innovative strategy: enhancing the absorption of these biologics by reprogramming adult enterocytes that mimic features of neonatal LRE, with high protein absorption.

· Deregulation of the metabolism of immune cells, such as T cells, seems key to the development of diseases such as cancer or autoimmunity. Despite the role of B lymphocytes in these diseases, little is known about how their metabolism is deregulated in pathological situations and more importantly, how this deregulation gives rise to disease. Our objective is to characterize the role of metabolism as a regulator of the activation and differentiation of B cells under normal physiological conditions, in order to later understand its role in the pathology and identify new biomarkers of the disease and possible therapeutic targets. We will use two different disease models, inflammatory bowel disease, and diffuse large B-cell lymphoma.

In summary, we hope that the combination of these gut-on-a-chip models with in vivo physiological systems will offer new ways to understand gut morphogenesis, patterning, homeostasis, and its relationship to human diseases such as cancer.

RESEARCH LINES

1. Characterize the role of lysosome-rich enterocytes (LRE) in the early stages of development, metabolism, and effect on intestinal homeostasis. IP: Fernando Martin Belmonte.

2. Cellular strategy to improve drug absorption for cancer treatment. IP: Fernando Martin Belmonte.

3. Characterize the role of B cell immunometabolism in the immune response. Nuria Martinez-Martin.

4. Characterize the role of smoothelin-like2 (smtnl2) in the reorganization of the cytoskeleton, and in the progression of carcinoma in intestinal tissues. IP: Fernando Martin Belmonte.

Location

Centro de Biología Molecular Servero Ochoa (CSIC-UAM)

(lab 120)

Universidad Autónoma de Madrid

C. Nicolás Cabrera, 1, 28049 Madrid

Phone: +34-911964721

E-mail: fmartin(ELIMINAR)@cbm.csic.es

Link to CBM-UAM group

Keywords

Cell polarity, epithelia, gut, morphogenesis, organoids, protein trafficking, cancer