H2020Индивидуална стипендия2020–2022

SoMuKT · SOmatic MUtagenesis in Kidney Tubule is enhanced by specific metabolic pathways

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-09-01 → 2022-09-26
Финансиране от ЕС: 183 473 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Генетичните мутации в клетките на бъбречните канали се анализират, за да се провери дали са свързани с промени в метаболизма на глутамина и амоняка. Разбирането на тези процеси помага да се разбере как се натрупват грешки в ДНК, които могат да доведат до рак.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

SOmatic MUtagenesis in Kidney Tubule is enhanced by specific metabolic pathways

Somatic genetic changes accumulate during a lifetime in every cell of the body and are a key factor promoting tumor initiation. Slowing down mutation accumulation could, in principle, reduce the risk of cancer. Unfortunately, our current knowledge about the processes and lifestyle factors that enhance mutation accumulation is very limited. Latest research has shown that different tissues and cell types display different mutation rates, which depend on cell-type-specific exposure to mutagens and ability to repair DNA lesions. In addition to differences in the number of mutations, cell-type-specific DNA-damage and repair also determine differences in the quality of mutations and produce recognizable mutational patterns and profiles. These patterns represent the mark that specific mutational processes leave on the genome and can be exploited to understand cellular mechanism leading to mutation. Having this in mind, we have studied single nucleotide variants (SNVs) and small insertions/deletions (indels) in normal cells derived from human kidney tubules. We have identified a subset of kidney tubule cells that showed a particularly interesting somatic mutation profile. Peculiar features included: -high mutation burden -direct correlation between mutation rate and transcription -specific alterations in the DNA strand-bias of SNVs Similar features have been observed in tumors with alterations of glutamine/ammonia metabolism. This branch of metabolism is involved in nucleotide synthesis and DNA repair. For these reasons, we hypothesize that similar alterations of glutamine/ammonia metabolism could be a mutational process occurring in normal kidney cells. This project objectives are: 1) test whether metabolic alterations similar to those observed in tumors occur in normal kidney tubule cells as well 2) assess whether similar alterations are the underlying cause of excessive mutation in a subset of normal kidney tubule cells 3) verify whether hypoxia signaling might be the driver of metabolic rearrangement connected with mutagenesis. Preliminary data in support of each point have been obtained.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

An important factor favoring cancer initiation is the lifelong accumulation of somatic mutations in the genome. In agreement, somatic mutations in a specific set of driver genes has been shown to drive the transition from a healthy cell to a tumorigenic clone in the kidney. The vast majority of kidney tumors originate from a specific segment of the kidney nephron, named proximal tubule (PT). However, the rate of somatic mutation accumulation before tumorigenic transformation in the kidney PT and the causes underlying this phenomenon are unexplored. Somatic mutation data can be used as a footprint to track the mutational processes that occurred in a specific cell during an individual´s lifetime. I established a protocol for reliable detection of somatic mutations in non-cancer human cells. I obtained whole genome data from clonally expanded single cells from skeletal muscle, kidney, fat and skin of healthy donors. My preliminary data point to an increased rate of somatic mutation accumulation during adult life in kidney PT compared to other kidney and non-kidney cells. PT cells showed a unique mutation pattern and distribution that enhances the chances of acquiring a driver mutation and tumorigenic traits. The very homogeneous pattern of somatic mutations in PT cells leads me to the hypothesis that the kidney PT is exposed to genotoxic compounds that are endogenously produced during physiological cellular activities. In particular, my data point to specific metabolic pathways, including 1) ammonia production, 2) aminoacid metabolism /reabsorption from the urine and 3) response to hypoxia. I will use cellular models to perturb the metabolic homeostasis of the kidney PT and test the effect on somatic mutagenesis and underlining mechanisms. My project will shed light on a mostly unexplored topic: how cellular metabolism can damage the genome over time and may have important implications for tumor prevention.

Оригинален текст от CORDIS (на английски).

Участници

OSPEDALE SAN RAFFAELE SRL · MilanoКоординаторИталия