Project Details
Projekt
Modulation of cyst growth in renal tissue from patients with autosomal dominant polycystic kidney disease in a human tissue-based 3D-in-vivo-model
Subject Area
Nuclear Medicine, Radiotherapy, Radiobiology
Nephrology
Nephrology
Term
from 2022 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 496538332
In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Cell proliferation and fluid secretion are two essential characteristics of cyst enlargement. Currently, there is still a need for therapies that inhibit cyst growth in order to preserve renal function in patients suffering from ADPKD. Recent data from our group has shown that cyst growth in an ADPKD mouse model is prevented by three different pharmacological inhibitors of transepithelial chloride secretion mediated by TMEM16A (Anoctamin 1). Furthermore, we have shown that hypoxia and subsequent activation of the hypoxia-inducible factor HIF-1α promotes cyst growth in our mouse model.Next, we aim to translate these findings into clinical application and our patients. As an important intermediate step, we need to test the most promising drugs with regard to their efficacy in human tissue. We have long-standing expertise using the 3D in vivo CAM (chorioallantoic membrane) model in the area of human tumor research and have established the CAM model to study the effects of different therapies (chemotherapy, radiation therapy) on tumor growth and angiogenesis. In addition to tumor tissue, we were successful in cultivating human ADPKD kidney tissue for more than a week and we were able to monitor cyst growth under various conditions. The model should enable us – in addition to animal- and cell culture models – to answer the following questions:1. What are the effects of inhibitors of chloride secretion (e.g. TMEM16A inhibitors, different concentrations) on cyst growth of human polycystic kidney tissue on the CAM? Do different parts of the kidney or individual ADPKD patients respond differently to certain drugs?2. What are the consequences of approved prolyl-hydroxylase inhibitors on cyst growth in the CAM model?3. Does cyst fluid composition have an impact on cyst enlargement? Which factors influence fluid composition and how can it be changed pharmacologically?4. Is it possible to culture mouse kidney slices on the CAM to study kidney (patho-) physiology which would offer a plethora of kidney-related analyses beyond polycystic kidney disease? With the proposed work, we aim to gain insights into the response of individual ADPKD patients to several drugs with different dosages. During the course of this process we hope to improve our understanding of the pathological mechanisms involved in ADPKD and identify novel pharmacological targets. In summary, the new methodology represents an important step in the development and testing of innovative therapeutic approaches and subsequently contributes to the reduction of animal experiments according to the 3R-principles („reduce, replace, refine“).
DFG Programme
Research Grants
