Ana Carolina Migliorini Figueira
Phone: +55 19 3512.1267
My research focuses on metabolism and hormone signaling control, particularly studying biochemical and structural aspects of nuclear receptors (NRs). The regulation of these proteins exists to promote a common control of gene expression in different tissues and developmental stages. These proteins are related to metabolic syndrome, diabetes, cardiopathies, cancer and obesity; acting in transcriptional regulation, generally, modulated by ligand binding. Data compiled show that medical prescriptions targeting nuclear receptors are increasing during the years. Today, these drugs account for over 30 billion dollars in pharmaceutical sales. In this context, the importance of these proteins as drug targets is evident. My current goal is to study the interactions between RNs, proteins, small molecules and DNA regulatory sequences aiming better understanding the mechanisms of action of NRs and their ligand modulation. These studies will be made by biochemical, biophysical and structural biology point of views.
Searching ligands for NRs.
The metabolic syndrome reaches at least 25% of world population, been characterized as a combination of pathologies like hypertension, obesity, diabetes, inflammation, and cardiopathies. Many efforts to combat this disease aim to modulate many nuclear receptors, like PPAR.
In this projects we intend o identify new molecules that can modulate NRs like Thyroid Hormone Receptor (TR) and Peroxissome Proliferator Activated Receptor (PPAR), which are directly involved in metabolic diseases like hypercholesterolemia, obesity and diabetes. Our goal is, through structural and biophysical studies, to identify molecules that selectively activate or represses these receptors. Also, for PPAR modulation, our research follows the new insight about PPAR phosporylation, discovered in 2009. This new approach postulates that is necessary to separate potency and agonism in PPAR case, in this way, the insulin sensitization is reached when the phosporylation is prevented.
- Prospection of ligands for PPAR – undergraduate student.
- Compounds identification for acting in diabetes control – undergraduate student.
- Inhibition of PPAR phosporylation – research assistant CNPEM.
Regulation of gene transrepression and transactivation modulated by Nuclear Receptors.
The RNs are closely related to diseases like cancer, metabolic syndrome, diabetes, cardiopathies and obesity. They can act directly or indirectly in the regulation of transcription. In the direct regulation, RNs activate or represses the gene expression though their ligand modulation (transactivation). The indirect process occurs when RNs acts under other transcription factors (transrepression). Many studies have shown the direct participation of RNs in the transcription activation and repression. Others reported the influence of interaction of TFs and some nuclear receptors in diverse proteins expression regulation processes.
In this context, the importance of a better understanding about the interaction among RNs and other proteins, besides the mechanisms of transactivation and transrepression, is evident. Furthermore, this project purposes the study of interactions between RNs and DNA regulatory sequences (HREs); RNs and coregulators proteins; and RNs and transcription factors. The results will be used in order to seek more information about their action mechanisms, allowing that new regulation models of transcriptional regulation mediated by NRs could be purposed. Or even, that the already purposed models could be shown in a higher degree of details.
- Transrepression and transactivation regulation mediated by nuclear receptors – Regular research project.
- Interaction among the nuclear receptors TR and PPAR and other cell proteins – PhD project.
- Expression, purification and search for complexes formed by nuclear receptors and associated proteins – Technical training.
- Cloning and sub cloning of nuclear receptors – research assistant.
- Expression and purification of nuclear receptors and initial characterization of proteic complexes – undergraduate student CNPEM.
- Validation of COUP-TF nuclear receptors DNA responsive elements in the SMyHC3 gene promoter.
Projects under Collaborations
-NRs and liker histones action under chromatin structure – colaboration with Prof. Dr. Guilherme Martins Santos and Prof. Dr. Franscisco de Assis da Rocha Neves.
-Interaction entre disulphide isomerase and GTPases: identification of proteic complexes – Pos doctorate fellow – collaboration with Prof. Dr. Francisco Rafeal Martins Laurindo and Dr.Ana Iochabel Soares Moretti.
-The function of nuclear receptors in the atrial specification – Master degree project – collaboration with Dr. Jose Xavier Neto and Barbara Pires.
Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange. Figueira AC, Saidemberg DM, Souza PC, Martínez L, Scanlan TS, Baxter JD, Skaf MS, Palma MS, Webb P, Polikarpov I. Mol Endocrinol. 2011 Jan;25(1):15-31.
Dissecting the relation between a nuclear receptor and GATA: binding affinity studies of thyroid hormone receptor and GATA2 on TSHβ promoter. ACM Figueira, I Polikarpov, D Veprintsev, GM Santos. PLoS One. 2010, 5(9):e12628.
FERM domain interaction with myosin negatively regulates FAK in cardiomyocyte hypertrophy. Santos AM, Schechtman D, Cardoso AC, Clemente CF, Silva JC, Fioramonte M, Pereira MB, Marin TM, Oliveira PS, Figueira AC, Oliveira SH, Torriani ÍL, Gozzo FC, Xavier Neto J, Franchini KG.Nat Chem Biol. 2011 Nov 20;8(1):102-10. doi: 10.1038/nchembio.717.
Gaining ligand selectivity in thyroid hormone receptors via entropy. Martínez L, Nascimento AS, Nunes FM, Phillips K, Aparicio R, Dias SM, Figueira AC, Lin JH, Nguyen P, Apriletti JW, Neves FA, Baxter JD, Webb P, Skaf MS, Polikarpov I.Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20717-22.
GQ-16, a Novel Peroxisome Proliferator-activated Receptor γ (PPARγ) Ligand, Promotes Insulin Sensitization without Weight Gain. Amato AA, Rajagopalan S, Lin JZ, Carvalho BM, Figueira AC, Lu J, Ayers SD, Mottin M, Silveira RL, Souza PC, Mourão RH, Saad MJ, Togashi M, Simeoni LA, Abdalla DS, Skaf MS, Polikparpov I, Lima MC, Galdino SL, Brennan RG, Baxter JD, Pitta IR, Webb P, Phillips KJ, Neves FA. J Biol Chem. 2012 Aug 10;287(33):28169-79.
|2000-2003||Graduation on Biological Sciences||Universidade Federal de São Carlos|
|2004-2008||PhD in Applied Physics – Biomolecular Option||Universidade de São Paulo – Instituto de Física de São Carlos – Laboratório de Cristalografia de Proteína|
|2009||Postdoctoral fellow||Universidade de São Paulo – Instituto de Física de São Carlos – Laboratório de Cristalografia de Proteína|
|2009||Postdoctoral fellow||University of Houston – Center for Nuclear Receptors and Cell Signaling/The Methodist Hospital.|
|2010||Postdoctoral fellow||Universidade de São Paulo – Instituto de Física de São Carlos – Laboratório de Cristalografia de Proteína|