Identification of physiological substrates for Nek1,4,6,8,10 and 11 , using a Shokat approach.

• Grant number: 24/04055-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2024
• End date: May 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Jörg Kobarg
• Grantee: Cintia Junia Monteiro
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 22/15126-9 - Two cell cycle regulatroy protein families: from functional studies to their use as novel diagnostic markers and therapeutic targets in cancer, AP.TEM

Abstract

Cancer is among the diseases that most kill humans and domestic animals. Depending on the tissue and cell type affected by mutations, a large number of sub-types of cancer can be differentiated. For a specific sub-type of cancer the molecular causes can be quite heterogeneous and for the majority of cases are poorly mapped. This represents both a major challenge as well as an an opportunity in the field, since an intense study of the molecular causes can lead to new diagnostic and therapeutic strategies. Protein kinases in signaling pathways and regulatory proteins in general, are frequently affected by activating or inactivating mutations in cancer and therefore contribute to cancer transformation. In this project we focus on two families of proteins with great potential of utility for both diagnostic and therapy in cancer. The first family consists of 6 members of the 11 members of the NEK protein kinase family, which are involved in the regulation of the cell cycle, mitosis, primary cilia function, DNA repair mechanisms and mitochondrial functions. The second family comprises the two human regulatory proteins, called HABP4 and SERBP1, that have roles in the regulation of transcription and gene expression, cell proliferation and the cells responses to stress. The central aim of this project is the study of the molecular functions of these proteins in the cell and the characterization of the effect of point mutations in their genes found in human cancers. Using immune-histochemistry and transcriptome analysis we will characterize theses proteins expression profile in cancer cells and the expression and regulation of mRNAs. This approach will allow us to identify for which cancer type each of the proteins studies serves as a molecular diagnostic marker and will also suggest new roads of therapeutical intervention. We will generate cell lines with gene knock out (Crispr Cas 9) and overexpression for these proteins, in for 2D and 3D, cell culture models. Furthermore, we will generate gene knock out models in relatively simple animal model organisms., such as C. elegans and zebra fish. Structural modeling and biochemical assays will allow the discovery and development of new inhibitors for the Nek protein kinases, providing new chemical probes for cancer treatment studies.