Research
Current Research Projects
Project 1: Molecular Mechanisms of Apoptosis
Our team is studying the basic mechanisms that control caspase-3, a key executioner caspase essential in apoptosis and immune cell fate. We have identified Hsp27 and PKCd as direct switches of caspase-3 activation. We use proteomics, biochemical, molecular biology and protein network analyses to study the contribution of post-translational mechanisms and protein-protein interaction in the regulation of caspase-3. We found that caspase-3 is essential in the regulation of innate immune cells using primary human and mouse monocytes and macrophages. We are currently investigating how caspase-3 regulates monocytes/macrophage function modulating tumor resistant and adipocyte function using 3D co-cultures and patient derived xenografts (PDXs). The goal of these studies is to determine how caspase-3 can be controlled to induce apoptosis in cancer cell and immune cells which numbers abnormally increase in chronic inflammatory diseases. This basic knowledge can be clinically translated and help control the number of immune cells abnormally present in the tumor and adipose microenvironment during chronic inflammatory conditions.
Project 2: Immune-Regulation: Establish the Protein and Gene Networks Responsible of Monocyte-Macrophage Immune Function
We are studying the molecular mechanisms that control monocyte numbers, differentiation into macrophages and macrophage switching (M1/M2). The goal of these studies is to establish the gene and protein hubs controlling monocyte-macrophage differentiation and their functions to therapeutically target monocyte/macrophage dysregulation characteristic of chronic inflammatory diseases including pathogen-induced inflammation, cancer and obesity. As part of these studies we use xenograft and genetically modified preclinical mouse models to study the immuno-regulatory mechanisms that control tumor evasion, cancer cell resistant and adipocyte dysregulation. RNAseq and proteomics analyses together with physiological and molecular biology approaches are used to elucidate the main pathways that control myeloid cell differentiation and apoptosis. The long-term goal of these studies is to understand the basic immune-regulatory mechanisms controlling monocyte/macrophage function.
Project 3: Flavonoids Targeting Inflammatory Diseases: Implications for Cancer and Obesity
Our team is studying the mechanisms responsible for the beneficial effects of flavonoids, phytochemicals broadly present in our diet. We found that dietary flavones decrease inflammation, tumor development and promote bacterial clearance. We are investigating the gene and protein networks modulated by flavonoids in innate immune cells, cancer cells and adipocytes using RNAseq and metabolic analyses. We use biochemical, analytical, cellular and preclinical mouse models of breast and lung cancer, bacterial infection and obesity. We have developed whole food formulations following approved food and technology guidelines that increase flavonoid absorption and delivered bioactive concentrations of flavonoids. These studies are aligned with a mission of promoting foods for health and sustainability. The goal of these studies is to better understand the mechanisms responsible for the anti-inflammatory and anti-carcinogenic activity of phytochemicals, and to trigger metabolic rewiring and reestablish immune balance key to human and animal health. New studies on the regulation of the microbiome and metabolic profiling are undergoing. These studies currently include human clinical trials for the prevention and treatment of chronic inflammatory diseases.
Project 4: Target Identification of Phytochemicals
To gain a better understanding of how phytochemicals exert their beneficial effects, our team has developed novel high-throughput genome-wide approaches, among them PDSeq, to identify direct protein targets of flavonoids. The implementation of PDSeq revealed a new mechanism by which the flavone apigenin, through direct association with RNA binding proteins, controls alternative splicing. We are using PDSeq in combination with RNASeq and metabolic network analyses to define therapeutic targets of flavonoids. In addition, high-throughput screening of compound libraries in combination with flavonoids are currently ongoing to identify best combinations for the prevention and treatment of cancer and other chronic inflammatory diseases.
Project 5: Control of Flavonoid Biosynthesis
Our team is pursuing genome-wide studies to establish the gene regulatory network responsible of flavonoid biosynthesis. For this purpose, we generated a maize transcription factor ORFeome collection that together with the use of yeast one hybrid and yeast two hybrid is helping define how transcription factors control the synthesis of phytochemicals. In addition, antibodies recognizing specific transcription factors are being developed and used in chromatin immunoprecipitation (ChIPs) and ChIP-Seq studies to further understand how flavonoid synthesis is regulated. In addition, we are studying the effect of stress conditions in transcription start sites of genes responsible for flavonoid biosynthesis using CAGE and ChIP-Seq. Together these studies will contribute to a better understanding of flavonoid synthesis. Findings from this project will facilitate the development of plants which are more resistant to pathogens and foods with higher levels of beneficial phytochemicals that can be used to improve human and animal health.
