Metab4 | Main Goals

Based on previously published work by several group members, as well as on the results from on-going research projects, the IMPg will focus on autoimmune diseases, neurodegenerative diseases and cardiovascular diseases.
In general, our scientific strategy will follow these successive steps:
1st- Identification of abnormal immunological and metabolic pathways that can be used as targets for new therapeutic strategies.
2nd- Development of drugs for modulation of altered immune and/or metabolic pathways and establishment of optimal drug delivery mechanisms.
3rd- In vitro and in vivo testing and validation of the new drug candidates.
4th- Patenting of the new drug candidates.

Autoimmune diseases: Rheumatoid Arthritis and diabetic retinopathy
Previous work of members of the group has shown that depletion of CD8 T lymphocytes leads to amelioration of experimental chronic arthritis. Furthermore, our data on rheumatoid arthritis patients show altered functionality of CD8 T lymphocytes. Thus, we have partnered with a biotech company, Hi-Tag Ltd, to develop an anti-CD8 based therapy. Testing of the drug on human samples will be done in partnership with Professor J.A. Pereira da Silva (Rheumatology Department, CHUC).
Since the inflammatory process in diabetic retinopathy shares similarities with rheumatoid arthritis synovitis, we are in the process of extending anti-CD8 therapy to diabetic retinopathy in collaboration with the team of Dr. A.F. Ambrósio from FMUC.

In previous studies members of the group have characterized whole body glucose homeostasis and determined the kinetics of de novo lipogenesis using stable isotope tracers (2H & 13C). These methodologies are nowadays well established for in vitro and in vivo studies, ranging from animal models to humans. A significant effort was also devoted to the development of optimal delivery mechanisms of insulin mostly based in its incorporation in micro- and nanoparticles, aiming at a controlled hormonal release. These have been tested in both type I and type II diabetes. Similar approaches are currently being tested for new generation anti-diabetic drugs.

Crohn’s disease
Our work on reactive oxygen species (ROS) deficient patients and animal models has provided evidence for the involvement of these molecules in the development of chronic colitis. We intend to use ROS modulating drugs developed by our group members E. Silva and F. Roleira either to prevent or reverse chronic colitis.

Neurodegenerative diseases: Alzheimer’s and Parkinson’s diseases
In the course of currently funded projects our group has found out that in both these neurodegenerative diseases B-lymphocytes are primed against central nervous system antigens leading to the production of autoreactive antibodies. These autoantibodies may induce microglial activation through Fc-gamma receptors, thus promoting chronic inflammation. Samples from patients will be made available by collaborators at the Neurology Department at CHUC: Drs C. Januário and I. Santana.
Using human monocyte-derived microglia (wild-type and infected with lentiviral vectors containing mutant LRRK2 or ApoE*4) and healthy human retinas (as an in vitro 3D model of the microglial micro-environment) we will test the therapeutic potential of Fc-gamma-blocking nanoparticles and ROS-modulating drugs in order to halt pro-inflammatory microglia activation and concomitantly neurodegeneration.

Cardiovascular Diseases
Energetic metabolism in the heart suffers dramatic changes under several complications. Left ventricular hyperthrophy, in particular, is characterized by a significant metabolic remodeling with a switch towards carbohydrate oxidation instead of the conventionally used fatty acids. Several drugs are capable of interfering with pyruvate dehydrogenase activity and modulate the coupling between glycolytic and oxidative metabolic pathways. Several drugs will be developed and tested for their capacity to induce metabolic remodeling and to improve overall heart hemodynamics.