Basic information: Orofacial anomalies are a diverse group of congenital malformations affecting jaws and teeth, which may occur in isolation (non-syndromic) or in their combinations (syndromic). In this project, we will focus on the mandibular hypoplasia in the orofacial region and we will analyze its association to dental hypodontia/oligodontia. We will evaluate clinical, radiological and genetic characteristics with aim to identify new candidate genes and their mutations involved especially in non-syndromic cases of these orofacial anomalies. As these jaw and tooth abnormalities can be diagnosed and recorded in detail during childhood, they can be further used to avoid later health complications. Interestingly, large number of gene mutations causing orofacial diseases were present also in oncological patients and found to be responsible for the induction of carcinogenesis, however current knowledge of associations of shared molecular features between orofacial anomalies and carcinogenesis is recently insufficient, providing an excessive space to discover new key findings to benefit patients and their families. Here, we will execute multidisciplinary approaches targeting shared molecular features of orofacial abnormalities and colorectal cancer. The obtained data can contribute to establishment of new screening algorithms targeting early detection of oncological disease in patients with jaws and teeth anomalies. For more detailed molecular analyses, we selected SATB2 as a candidate gene, whose mutations or changes in expression have been already associated with jaw hypoplasia and colorectal carcinoma. The usage of animal model (Satb2-deficient mice) will allow us to determine the cellular and molecular processes involved in the development of these two pathologies and to establish the model for following tests to screen new treatments.

Registrtion No: NW24-10-00204

Project duratin: 1. 5. 2024 – 31. 12. 2027

Principal investigator: Doc. RNDr. Marcela Buchtová, Ph.D.   Institute of Animal Physiology and Genetics CAS, v. v. i.

Other solver: MUDr. et MUDr. Jan Štembírek, Ph.D.  University Hospital Ostrava

Other solver: Prof. MUDr. Lydie Izakovičová Hollá, Ph.D.   St. Anne’s University Hospital Brno 

Other solver: RNDr. Ing. Ondřej Bonczek, Ph.D.      Masaryk Memorial Cancer Institute

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Basic information: Osteoporosis is a metabolic bone disease with increasing prevalence in the elderly population associated with low bone mass rising the risk of fragility fractures. It is one of the serious risk factors affecting a lifetime of the implant in the body, associated with an increased number of revision surgeries. A solution for better implant fixation in osteoporotic bone could be creation of gyroid porous system on its surface. This system provides better mechanical interlock offering a larger surface area ensuring a more favourable and stronger bone-implant contact. Gyroid structure formed by walls with interconnected pores is characterized by high strength and low modulus of elasticity similar to human cancellous bone. In this project 3D printed gyroid structures with gradient elastic properties will be tested in contact with the osteoporotic bone. For this purpose, two titanium alloys, conventional (Ti6Al4V) and advanced (Ti25Nb4Ta8Sn), characterized by lower stiffness, will be used. The gyroid structures will be designed according to mathematical models so that the pore size is variable from the surface of the implant towards its solid core. Developed 3D printed structures will be analysed in terms of the occurrence of defects caused by 3D printing and mechanically tested. Furthermore, in vitro tests and two phases of in vivo tests will be performed on an animal model (5 osteoporotic minipigs + 3 healthy minipigs as a control per 1 in vivo test). Bone ingrowth into the gyroid with different pore sizes created from the conventional Ti6Al4V alloy (1st in vivo test) and bone ingrowth into the optimal porous gyroid structure, established in the first phase, created by the types of tested alloys (2nd in vivo test) will be monitored. Knowledge of the bone tissue ingrowth into the gyroid structures and the results of histological analyses will enable a design of the optimal porous surface of the implant with a high degree of osseointegration in osteoporotic tiss.

Registrtion No: NW24-10-00118

Project duratin: 1 .5. 2024 – 31.12. 2027

Principal investigator: MUDr. MDDr. Martin Bartoš, Ph.D.       General University Hospital in Prague

Other solver: MVDr. Jana Juhásová, Ph.D.      Institute of Animal Physiology and Genetics CAS, v. v. i.

Other solver: Ing. Zdeněk Tolde, Ph.D.    CTU in Prague / Faculty of mechanical engineering

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Basic information: Inherited retinal diseases are a genetically heterogeneous group of rare eye disorders with a progressive manifestation causing vision loss, affecting approximately one in 2,000 individuals worldwide. An increasing number of genes have been associated with inherited retinal degeneration, yet the understanding of their function in retinal biology is very limited. Bardet-Biedl syndrome (BBS) is a systemic, rare autosomal-recessive ciliopathy, with a prevalence around 1:150,000 in North America and Europe. This makes BBS the most common non-lethal ciliopathy involving early onset visual impairment. Efforts have been made to develop an early intervention to treat the inherited retinal degeneration diseases including BBS, with minimal success so far. The main objective of the proposed research is to characterize the molecular pathogenesis of retinal degeneration in BBS, and to suggest a suitable pharmacological intervention. We hypothesize that the progressive photoreceptor death in BBS is a consequence of their long-term ER stress, and that identification of the involved response pathways and their pharmacological modulation may prevent the disease onset and progression. Because the mouse models do not faithfully recapitulate many characteristics of the human BBS disease, mostly due to interspecies differences, we will take advantage of the human induced pluripotent stem cell-derived retinal organoids and retinal pigmented epithelium cells in order to develop a high-throughput system for functional diagnostics of specific mutations present in BBS, and for their targeted pharmacotherapy. Cíle projektu anglicky The main objective of the proposed research is to develop a high-throughput system in order to characterize the molecular pathogenesis of retinal degeneration in BBS, and to suggest a widely applicable pharmacological intervention. The following specific aims will address the objective: 1) To generate hiPS cells carrying specific BBS mutations. 2) To characterize the ciliary defect caused by BBS mutation using hiPS cell-derived RPE cells. 3) To define the photoreceptor phenotype in retinal organoids produced from BBS hiPS cells. 4) To screen for a pharmacological treatment of BBS using retinal organoids and RPE cells. The proposed research has a clear application potential, as we aim to develop a unique screening platform, and to suggest a novel treatment for so far incurable human genetic condition.

Registrtion No: NU22-07-00380

Project duration: 1. 5. 2022 – 31. 12. 2025

Principal Investigator: Mgr. Tomáš Bárta, Ph.D.  Masaryk University

Other solver: Mgr. Michaela Bosáková, Ph.D. Institute of Animal Physiology and Genetics CAS, v. v. i.

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Basic information: In a large proportion of patients operated for Crohn's disease, there will be a recurrence and the development of stenosis in the area of intestinal anastomosis. Drug treatment in these cases is usually ineffective and patients need to be reoperated. New endoscopic techniques could delay or eliminate the need for rerection, thereby improving the quality of life of patients and reducing the cost of treatment. The expected benefit of the project is an experimental evaluation of the effect of introducing a self-expressed stent into the site of stenosis in recurrence of Crohn's disease in the field of enterocolic anastomosis, including the design of a functional therapeutic algorithm. During the project, the potential of endomicroscopy in evaluating the effect of endoscopic treatment will be further evaluated. The project supports the development of new minimally invasive techniques with the aim of reducing the risk of postoperative complications and reducing the need for hospitalization by transferring treatment to an outpatient regimen.

Registrtion No: NU22-08-00554

Project duration: 1. 5. 2022 – 31. 12. 2025

Principal Investigator: MUDr. Ondřej Ryska, Ph.D. Institute of Animal Physiology and Genetics CAS, v. v. i.

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Basic information: Infectious complications associated with diabetic foot(DF) not only increase the morbidity of DF patients,but also the economic demands arising from hospitalisations and amputations.Instances of amputation due to DF infection can be prevented by administering antibiotic(ATB)therapy at levels conducive to optimal bactericidal activity in serum and tissue.However,time-dependent ATBs are not routinely monitored in DF patients.The aims of this project are to analyse the serum and tissue concentrations of beta-lactam and cephalosporin ATBs administered under different dosing regimens, and to evaluate bactericidal and clinical effects on parameters of infection in DF patients at various stages of peripheral arterial disease.We will monitor ATB effects on the gastrointestinal tract(GIT),particularly changes in the microbiota and intestinal barrier,while determining the optimal ATB dosing regimens required for increasing microbicidal effects and reducing GIT side-effects.Our study introduces a novel approach to preventing infection progression and reducing amputation rates in DF patients.

Registrtion No: NU20-01-00078

Project duration: 1. 5. 2020 – 31. 12. 2023

Principal investigator: MUDr. Vladimíra Fejfarová, Ph.D.  Institut for Clinical and Experimental Medicine

Other solver: Ing. Jakub Mrázek, Ph.D.                  Institute of Animal Physiology and Genetics CAS, v. v. i.

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