Novel insights into the pathophysiology of growth retardation and other endocrine conditions: Lessons learned from consanguineous and non-consanguineous families

• Název práce v češtině: Nové pohledy na patofyziologii růstové retardace a dalších endokrinních poruch: Poznatky z konsanguinních a non-konsanguinních rodin
• Název v anglickém jazyce: Novel insights into the pathophysiology of growth retardation and other endocrine conditions: Lessons learned from consanguineous and non-consanguineous families
• Klíčová slova: růstová retardace; endokrinní porucha; děti; genetika; konsanguinita
• Klíčová slova anglicky: growth retardation; endocrine condition; children; genetics; consanguinity
• Akademický rok vypsání: 2018/2019
• Typ práce: disertační práce
• Jazyk práce: angličtina
• Ústav: Pediatrická klinika (13-350)
• Vedoucí / školitel: prof. MUDr. Jan Lebl, CSc.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 08.10.2018
• Datum zadání: 16.10.2018
• Datum potvrzení stud. oddělením: 16.10.2018
• Datum a čas obhajoby: 15.02.2024 10:00
• Datum odevzdání elektronické podoby: 07.01.2024
• Datum odevzdání tištěné podoby: 07.01.2024
• Datum proběhlé obhajoby: 15.02.2024
• Oponenti: doc. MUDr. Jiřina Zapletalová, Ph.D.
• Konzultanti: prof. MUDr. Štěpánka Průhová, Ph.D.

Seznam odborné literatury

Min Jae Kang, Novel genetic cause of idiopathic short stature, Ann Pediatr Endocrinol Metab 2017; 22: 153-157
Andrade A, C, Jee Y, H, Nilsson O, New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth. Horm Res Paediatr 2017; 88: 22-37

Předběžná náplň práce

Background. Height and body proportions of humans are mainly determined by bone growth. Longitudinal bone growth occurs at the growth plate, where resting chondrocytes convert into proliferating chondrocytes, then hypertrophic chondrocytes, finally undergoing apoptosis before eventually being replaced by bone tissue.
Normal growth requires adequate nutrition, physiological balance of the immune system; normal hormonal signalling including the GH–IGF-I axis, thyroid hormones, glucocorticoids and sex hormones, but it requires normal local signalling within the epiphyseal growth plate as well. Recent studies have contributed to the understanding of growth regulation, showing that multiple factors which are independent from the GH – IGF-I system regulate chondrogenesis in the growth plate. These are factors including paracrine signalling, extracellular matrix formation and integrity of fundamental cellular processes.
Aim. The aim of the proposed project is to elucidate the pathophysiology of growth retardation and some additional endocrine conditions in a unique cohort of consanguineous families using current techniques of genetic and physiological research, therefore contributing to the general understanding of the physiological regulation of a child’s growth and development.
Study population. All consanguineous families presently included in the cohort comprise of one or more children with endocrine disorders ranging between the ages of three months to eighteen years. Among this group, there are currently twenty-five families with children who have growth retardation (out of these, seventeen have been clinically classified as idiopathic short stature, eight as growth hormone deficiency - two of which have dysmorphic features as well). Fourteen consanguineous families have children with other endocrine conditions such as hypogonadism, adrenal diseases and beta-cell disorders.
Hypothesis and expected outcomes. Consanguinity within the families clearly suggests that a single-molecule mechanism is the pathophysiological mechanism of the individual conditions. Therefore, consanguineous families provide the best chances to successfully encounter novel genes which have a close link to metabolic and/or endocrine conditions.
Inspite of the fact that the research methods will commence with a genetic approach (analysis of data obtained by whole exome sequencing methods), the true nature of the project will be the elucidation of novel pathophysiological pathways of developing disease. Studying the function of a mutated protein on a molecular basis, and its cellular functions on cell cultures, has the potential to facilitate understanding of the protein function and its link to human disease. The project has the unique potential to obtain samples from consanguineous families with the possibility to return to the patient and study the phenotype more deeply with focus on specific issues. In addition, the study will be conducted in a laboratory which has significant experience with functional studies on cell lines. Moreover, the lab is in close collaboration with the Věra Vávrová Laboratory (LVV), where protein-protein interactions can be studied and animal models can be prepared.
The study strives to prove the hypothesis that, in consanguineous families with apparent phenotypes, it may be possible to successfully elucidate novel mechanisms of growth retardation at the level of the chondrocyte and, in parallel, novel mechanisms in some other endocrine conditions as well. If successful, identifying new genetic causes and pathophysiological mechanisms has the potential to improve diagnosis, personalised management and prognosis.
We hypothesise that most of the molecular mechanisms in the affected children will be already known, but some may be new and thus may extend the general knowledge and understanding on the regulation of growth, pathophysiology of growth retardation and some other endocrine disorders. In conclusion, this project has the potential to bring about novel insight to pathophysiology of human endocrine disease.

Předběžná náplň práce v anglickém jazyce

Background. Height and body proportions of humans are mainly determined by bone growth. Longitudinal bone growth occurs at the growth plate, where resting chondrocytes convert into proliferating chondrocytes, then hypertrophic chondrocytes, finally undergoing apoptosis before eventually being replaced by bone tissue.
Normal growth requires adequate nutrition, physiological balance of the immune system; normal hormonal signalling including the GH–IGF-I axis, thyroid hormones, glucocorticoids and sex hormones, but it requires normal local signalling within the epiphyseal growth plate as well. Recent studies have contributed to the understanding of growth regulation, showing that multiple factors which are independent from the GH – IGF-I system regulate chondrogenesis in the growth plate. These are factors including paracrine signalling, extracellular matrix formation and integrity of fundamental cellular processes.
Aim. The aim of the proposed project is to elucidate the pathophysiology of growth retardation and some additional endocrine conditions in a unique cohort of consanguineous families using current techniques of genetic and physiological research, therefore contributing to the general understanding of the physiological regulation of a child’s growth and development.
Study population. All consanguineous families presently included in the cohort comprise of one or more children with endocrine disorders ranging between the ages of three months to eighteen years. Among this group, there are currently twenty-five families with children who have growth retardation (out of these, seventeen have been clinically classified as idiopathic short stature, eight as growth hormone deficiency - two of which have dysmorphic features as well). Fourteen consanguineous families have children with other endocrine conditions such as hypogonadism, adrenal diseases and beta-cell disorders.
Hypothesis and expected outcomes. Consanguinity within the families clearly suggests that a single-molecule mechanism is the pathophysiological mechanism of the individual conditions. Therefore, consanguineous families provide the best chances to successfully encounter novel genes which have a close link to metabolic and/or endocrine conditions.
Inspite of the fact that the research methods will commence with a genetic approach (analysis of data obtained by whole exome sequencing methods), the true nature of the project will be the elucidation of novel pathophysiological pathways of developing disease. Studying the function of a mutated protein on a molecular basis, and its cellular functions on cell cultures, has the potential to facilitate understanding of the protein function and its link to human disease. The project has the unique potential to obtain samples from consanguineous families with the possibility to return to the patient and study the phenotype more deeply with focus on specific issues. In addition, the study will be conducted in a laboratory which has significant experience with functional studies on cell lines. Moreover, the lab is in close collaboration with the Věra Vávrová Laboratory (LVV), where protein-protein interactions can be studied and animal models can be prepared.
The study strives to prove the hypothesis that, in consanguineous families with apparent phenotypes, it may be possible to successfully elucidate novel mechanisms of growth retardation at the level of the chondrocyte and, in parallel, novel mechanisms in some other endocrine conditions as well. If successful, identifying new genetic causes and pathophysiological mechanisms has the potential to improve diagnosis, personalised management and prognosis.
We hypothesise that most of the molecular mechanisms in the affected children will be already known, but some may be new and thus may extend the general knowledge and understanding on the regulation of growth, pathophysiology of growth retardation and some other endocrine disorders. In conclusion, this project has the potential to bring about novel insight to pathophysiology of human endocrine disease.