Research in modern biology typically requires integrated experimental approaches. In line with this, research at IBPM is strongly multidisciplinary, combining wet-lab assays and computational predictions to expand current knowledge of the molecular mechanisms underlying complex biological processes and develop novel biotechnological and nanotechnological applications relevant to human health, agrifood, and the environment.
The research topics developed at IBPM encompass the structure and function of nucleic acids and proteins, regulation of gene expression, control of differentiation and cell division, the immune response, and the mechanisms of interaction between living organisms and the environment. These aspects are tackled in their complexity using highly diversified expertise and methodologies, as well as an array of biological models, Our studies unfoled at several levels: from the design and synthesis of bioactive molecules, to the structural and molecular characterization of macromolecules and cellular systems, to the organismal level in entire animal and plant models.
A) HUMAN HEALTH
The emphasis of IBPM projects in this field is on the genetic and molecular mechanisms underlying physiological and pathological processes, with the goals to i) identify early diagnostic markers and novel molecular targets, and ii) develop innovative preventive and therapeutic tools for diseases with a high societal impact. Research lines can be grouped in three broad areas.
1. The immune system and infectious diseases
1.1. A common goal of research in this field is to rationalise innovative strategies to fight drug-resistant infections, develop new antimicrobial compoundsand, and prevent and treat infectious and immuno-mediated diseases.
To identify potential pharmacological targets in human pathogenic microorganisms, several studies focus on the structural and functional characterization of proteins from pathogenic bacteria (Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Escherichia coli) and protozoa (Leishmania infantum). These proteins modulate microbial virulence via their crucial contributions to genome architecture, gene expression and protein synthesis, energy and cofactor metabolism, redox homeostasis, and metal transport. Several approaches ('rational design', experimental and 'in silico' screening) are being adopted to identify inhibitors of potential pharmacological interest. In addition, protein engineering methodologies are employed to characterise, structurally and functionally, key enzymes to produce new antibiotics.
1.2. Research in the field of innate and adaptive immunity aims at deciphering the molecular and cellular mechanisms underlying protective immune responses (e.g. vaccines) as well as damage-inducing ones in immuno-mediated pathologies (e.g. psoriasis). The emphasis is on the response of "memory" CD8 T-lymphocytes and on the development and homeostasis of dendritic cells and 'natural killer' cells.
2. The nervous system, neurological and neuromuscular diseases
Research studies in this area focus on the pathogenetic mechanisms of high societal impact diseases of the nervous and muscular systems, e.g. Duchenne muscular dystrophy, Alzheimer's disease, spinal muscular atrophy, primary and amyotrophic lateral scleroses, autism, anxiety disorders, hereditary spastic paraplegia, Down syndrome, Huntington's disease, early infantile epileptic encephalopathy, and other rare neurological diseases.
Several model systems are used (mouse neuronal primary cell cultures; stem cells and myogenic cells derived from human patients; and model organisms, e.g. Drosophila), aiming to gain insight into the role of coding and non-coding RNAs (miRNA, lncRNA e circRNA) in these pathologies and in neuronal homeostatic regulatory circuits (e.g., response to stress hormones). A set of highly interesting biochemical studies address the role of native, mutant and oxidatively-modified proteins, as well as hydrogen sulfide and glucose metabolism, in favouring neurodegenerative and neurodevelopmental diseases. Further investigations focus on the predictive value of human genetic polymorphisms as markers for age-related neuropathological conditions and on the impact of cognitive processes on gene expression under physiological conditions.
3. Cellular homeostasis and molecular oncology
Several studies are aiming to investigate basic processes underlying cancer onset or progression, and design innovative therapeutic strategies.
3.1. Investigating the molecular errors that can evolve to contribute relevant cancer hallmarks; more specifically:
- epigenetic plasticity, associated with histone acetylation /methylation, and the roles of non-coding RNAs;
- the induction of genetic instability originating from defects in control of mitosis;
- the role of molecular factors underlying intracellular heterogeneity in the induction of drug resistance and in response to therapeutic treatments;
- the metabolic reprogramming of cancer cells;
- the mechanisms of the immune response and tumor angiogenesis.
3.2. Research on novel pharmacological targets and their inhibitors.
This line of research is particularly active at IBPM; it builds upon established expertise in methods for the structural and functional characterization of proteins, bioinformatic analyses and chemistry - including the synthesis of molecules and compounds. The integration of these approaches provides the grounds for drug-discovery strategies. An advanced level of development has been reached in the design and synthesis of bioactive molecules, inhibitors, as well as nanovectors and biomaterials for drug delivery (see below, Biotechnology applications, for further details).
B) ENVIRONEMENT AND AGRIFOOD
IBPM groups are developing several research projects addressing the interactions between living organisms and the environment. A variety of experimental approaches and biological systems are being used with the aim to obtain plant varieties that can offer competitive advantages in agriculture, food safety and monitoring of pollution effects on human health.
In studies using the Arabidopsis thaliana model, new plant varieties resistant to different types of environmental stresses have been isolated and male-sterile plants have been obtained. A special focus is being developed in studies regarding:
i) Transcription factors of the HD-Zip group (homeodomain-leucine zipper proteins) and their role in the development of plant organs and in signalling networks determining the auxin /cytokinin-mediated adaptive response to light; understanding these responses is relevant to define modes of agricultural sustainability.
ii) Molecular mechanisms regulating auxin- and environment-mediated gene expression in the development of male reproductive organs.
Research on food safety concentrates on the inhibitory effect of synthetic polyphenolic compounds on the growth of molds contaminating foodstuffs and on the biosynthesis of mycotoxins (e.g. Aspergillus flavus and aflatoxins).
Environmental studies also include projects aiming at evaluating the impact of pollution by analyzing the effect of atmospheric particulate matter on gene expression in human cells.
C) BIOTEHCNOLOGY APPLICATIONS
Several IBPM research lines have a high translational potential, particularly in the fields of drug delivery and phytoremediation.
1. Innovative design and optimization of 'drug delivery' systems along several lines
- Development of engineered nanovectors based on human ferritin for the effective transport of anti-tumor drugs. In vivo studies have already established that these nanosystems, loaded with chemotherapeutic agents, can selectively target tumor cells of different histological origin;
- New gene therapy protocols based on the design and development of adeno-associated viral vectors (AAV) to re-program tissue-specific gene expression. This technology is being used to transport artificial transcription factors in an innovative therapeutic approach to treat Duchenne muscular dystrophy.
- Development of a novel methodology to incorporate specific interfering RNAs (siRNA and miRNA) into membrane microvescicles (exosomes), to be used as novel therapeutic tool against HPV-related tumors;
- Innovative methods to produce new biomaterials, e.g. DNA hydrogels and other functionalized nanostructured materials, to transport bioactive molecules and enzymes towards target tissues.
Hyperaccumulating plant species are being studied for their remediation potential towards soil contamination by arsenic or heavy metals. A specific technique has been developed that can rapidly and non-destructively assess the progressive accumulation of arsenic by X-ray micro fluorescence.
3. Organic syntheis and design
An additional research activity concerns the synthesis of several classes of organic compounds (in particular polyphenolic and heterocyclic ones) that are functionalized with antioxidant and antimicrobic activities, of potential pharmacological interest.
In some cases, some of the projects listed above have already reached an advanced stage of application with a solid perspective of developing public-private partenarships.