The overall objective of the In Vivo Models Resource (IVMR) in the UAB Childhood Cystic Kidney Disease Center
(CCKDC) is to facilitate research into the mechanisms driving renal cystogenesis that will accelerate translation
of basic discoveries into clinical care for PKD patients. The IVMR is accomplishing this objective through the
generation, application, and distribution of PKD relevant animal models and biosensors for pathways associated
with cystic kidney disease. As described in the original application, the IVMR is generating and making available
to the PKD Consortium multiple mouse, zebrafish, and rat models for PKD. However, based on feedback and
requests from scientists in the PKD research field, there is a need for additional resources that are not included
in the original proposal. Thus, in the absence of this supplemental request, we will not be able to generate these
new model systems. This includes:
1) Mouse embryonic stem cells and human induced pluripotent stem cells (iPSCs) wherein self-labeling
tags are incorporated into the PKD proteins and can be subsequently genetically modified to express
patient relevant variants to generate the mouse models and use in organoid studies.
2) A series of mouse cAMP biosensors based on new technology that can detect changes in cAMP levels
initiated in either the cilium or cytosol.
3) New mouse models that will allow synthetic ligand induced cAMP production in either the cytosol or cilia
to evaluate cAMP signaling during cyst development.
The resources made available through this administrative supplement will be generated and distributed through
the PKD Consortium as soon as they are available. They will provide new opportunities for PKD researchers to
visualize the PKD proteins in live samples, including in vivo in live kidneys, to test how patient variants alter
protein stability, transport, localization, interactions, membrane insertion, etc. The cAMP biosensors will facilitate
research into where cAMP concentrations change in the cell in relation to the primary cilium and during cyst
development. Finally, the cAMP induction system will address a critical question of whether cAMP originating
from the cilium or cytosol is important in cyst formation. Collectively, the new research opportunities resulting
from the resources will advance the pace of research into the cellular and molecular basis of renal cyst formation,
will help focus stratigies to treat the disease, and will be the basis for new models for preclinical testing.