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The influence of expression and polymorphism of proinflammatory genes on kidney transplant outcome
Hřibová, Petra ; Vyklický, Ladislav (advisor) ; Jirsa, Milan (referee) ; Stříž, Ilja (referee)
Acute rejection and chronic transplant nephropathy are the main complications after kidney transplantation. A broad spectrum of cytokines, chemokines and growth factors are involved in their etiology. The aim of this submitted dissertation was to find the influence of polymorphisms in selected genes and their intrarenal expression on kidney graft outcome. All studies were designed to follow a large cohort of individuals in order to be able to elucidate some unclear and inconsistent published results. 1. Cytokines and chemokines TGF-β1, TNF-α, IL-6, IL-10, MCP-1 and RANTES are up-regulated in different rates in acute rejection, chronic transplant nephropathy and also in other causes of kidney graft dysfunction. 2. High intrarenal expression of TGF-1 and MCP-1 mRNA in CAN predicts a higher risk of kidney graft dysfunction in the long-term. Also, the kidney graft survival is significantly shorter. 3. Intrarenal gene expression profile of TGF-1, TNF-, IL-6, IL-10, MCP-1 and RANTES is different during various causes of graft dysfunction. The intrarenal expression level cannot be used for diagnostic purposes, but it can alert higher immunological activity in kidney graft, which can lead to earlier failure of renal functions. 4. We did not confirm an association of TNF--308G/A, MCP-1 -2518 A/G, RANTES-...
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Molecular Basis of Familial Hyperuricemic Nephropathies
Živná, Martina ; Kmoch, Stanislav (advisor) ; Jirsa, Milan (referee) ; Sedláček, Zdeněk (referee)
In 1960 Duncan and Dixon described family whth chronic tubulointerstitial kidney disease associated with juvenile onset of hyperuricemia and gout. Based on combination of these clinical symptoms they named the disease familial juvenile hyperuricemic nephropathy (FJHN) [1]. Disease with very similar clinical presentation but different age of onset and kidney histology was described as a medullary cystic kidney disease (MCKD) in 1977 [2]. Until recently the molecular basis and pathogenesis of this syndrome remained unknown. The long term aim of our research group is to elucidate the genetic basis of the disease and to solve pathogenetic mechanisms leading to the individual clinical and biochemical symptoms (e.g. hyperuricemia) and kidney damage in general. We systematically identify patients with this disease and healthy family members and collect relevant clinical information and samples for classification (urine, blood, tissue biopsies) and subsequent clinical, biochemical, molecular biology and cell pathology correlations. We [3, 4] and others [5-7] proved genetic heterogeneity of FJHN and defined four FJHN loci on chromosomes 1q21, 1q41, 16p11.2. and 17q21.3. Further research defined disease causing mutations in three genes - uromodulin (UMOD) [8], hepatonuclear factor 1-beta (HNF-1) [9] and renin (REN)...
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Molecular Basis of Hereditary Hyperuricaemic Nephropathies
Vyleťal, Petr ; Kmoch, Stanislav (advisor) ; Viklický, Ondřej (referee) ; Jirsa, Milan (referee)
Familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2) are autosomal dominant tubulointerstitial nephropathies characterized by combinations of hyperuricaemia, gouty arthritis, progressive renal insufficiency, and in some but not all families, medullary cysts. The phenotypic expression of these diseases is inconsistent, overlaps and indicates broader genetic and allelic heterogeneity. Their pathophysiology was mainly unknown. Previous studies localized FJHN/MCKD genes to chromosomes 16p11 and 1q21. This thesis was primarily aimed at identification of molecular bases and mechanisms underlying FJHN/MCKD. To follow this aim, we focused on collection and characterization of FJHN/MCKD patients and families, identification of disease causing genes in affected families, characterisation of identified proteins and their mutated forms and the isolation and characterisation of interacting partners of newly identified proteins. We employed and established numerous molecular genetic, molecular biological and biochemical methods. We gathered one of the largest sets of families with FJHN/MCKD in the world. In about 26% of families we identified UMOD (uromodulin encoding) gene mutations and characterised by various approaches 6 uromodulin mutant proteins....
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