H2020Индивидуална стипендия2019–2021

ROAR · Role of endocycle in Acute Kidney Injury Response and Chronic Kidney Disease development

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

Период: 2019-09-01 → 2021-08-31
Финансиране от ЕС: 171 473 €
Участници: 1
Схема: MSCA-IF-EF-RI

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Накратко на български

Механизмите на полиплоидия изследват как бъбречните клетки увеличават количеството ДНК след остро увреждане. Разбирането на този процес помага за ранното откриване на пациенти с риск от развитие на хронична бъбречна болест.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Role of endocycle in Acute Kidney Injury Response and Chronic Kidney Disease development

Acute Kidney Injury (AKI) is characterized by an acute deterioration of kidney function impacting million patients per year. The cost of AKI-related inpatient care is estimated to be higher than that of the four most common cancers combined. In addition, AKI survivors frequently develop chronic kidney disease (CKD) which is associated with a high cardiovascular risk and progression toward end stage kidney disease (ESKD). CKD contributes a substantial proportion of disease burden globally. Yet over the past 30 years the burden of CKD has not declined to the same extent as many other important non-communicable diseases (i.e. cardiovascular and cancer-related diseases) implying a substantial deficit in the understanding of the disease progression. Recently, it has been described that kidney cells respond to AKI by triggering endocycle-mediated polyploidization. Polyploid cells derive from alternative cell cycles that lead to the formation of hypertrophic cells with an increased DNA content. The discovery that polyploidy occurs within the kidney after AKI has revolutionized our understanding of how the kidney responses to an injury. However, the mechanisms controlling kidney polyploidization have been completely unknown until recently. Collectively the objectives of this project were: 1) to uncover the mechanisms governing polyploidy in the kidney; 2) to establish the importance of polyploid cells for patient’s survival after AKI; 3) to determine the role of polyplod cells in the progression of AKI to CKD and 4) to design novel tools for early detection and stratification of patients at risk of developing CKD after AKI. The results obtained in this project have identified the pathways that control polyploidization of kidney cells. Importantly, these data proved that after AKI, polyploid cells are required to sustain kidney function and that they are essential for survival. Finally, polyploid cells were found to be involved in the formation of scar tissue after AKI promoting CKD progression. This important result was also confirmed in kidney biopsies of CKD patients representing an important translational output. Finally, one essential feature of this project is the translation of this knowledge to novel promising therapeutic and diagnostic approaches to CKD progression and management of AKI patients. Consequently, these efforts will have a potential positive impact for both patients and public health.

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

Цел на проекта

Acute kidney injury (AKI) is a global public health concern which results in 1.7 million deaths per year. If not lethal in the acute phase, AKI is considered reversible as suggested by recovery of renal function. However, even mild AKI episodes carry substantial risk of developing subsequent chronic kidney disease (CKD). The pathophysiological basis for this phenomenon remains unclear. Injury and death of tubular cells are recognized as the main factors in the pathogenesis of AKI and functional recovery from AKI was traditionally attributed to the regenerative capacity of tubular epithelial cells (TECs) which are believed to re-enter the cell cycle and repair the damage. Nevertheless, my preliminary data provide evidence that an endocycle-mediated response of remnant TECs may represent a critical mechanism of response to AKI. Endocycles are cell cycle variants consisting of G and S phases alone that repeatedly proceed without cytokinesis and its role in repair of mammalian tissues is mostly unknown and totally unexplored in the kidney. This proposal will be structured into 3 distinct objectives to address: 1. The physiologic relevance of endocycle for kidney function recovery after AKI 2. The role of endocycle in the progression of AKI to CKD; 3. The mechanism by which YAP1 drives endocycle and contributes to CKD development. To this end I will use lineage tracing techniques based on the FUCCI2aR reporter applied in different transgenic animal models of AKI, together with in vitro experiments in human primary cultures of renal tubular cells.Collectively, the outcomes of this proposal are expected to provide an entirely novel view of the kidney’s response to AKI, to further our understanding of the processes that drive CKD following AKI, as well as to describe for the first time endocycle as a critical response mechanism to tissue injury in the mammalian kidney.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITA DEGLI STUDI DI FIRENZE · FlorenceКоординаторИталия