# In vivo Pathway Discovery in Autosomal Dominant Polycystic Kidney Disease

> **NIH NIH RC2** · YALE UNIVERSITY · 2022 · $1,289,362

## Abstract

Abstract Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic
diseases, affecting >1:1000 individuals worldwide. It is characterized by large fluid-filled renal cysts that remodel,
compress and destroy surrounding normal tissue, and that progressively reduce kidney function, leading to end
stage renal disease in about 50% of patients by the sixth decade of life. Most ADPKD results from mutations in
two genes, PKD1, which encodes the polycystin-1 protein (PC1), and PKD2, which encodes the polycystin-2
protein (PC2). PC1 and PC2 interact with one another and are thought to play a role in cilia signaling. It is
generally accepted that the cilium is a central component in the pathways that drive ADPKD pathogenesis.
Although their mechanistic connection to the functional PC complex in cilia is unclear, numerous signaling
pathways are perturbed in cysts. In the past few years the list of disease-related pathways has grown through
new evidence that implicates metabolism as a novel pathway that is profoundly affected in ADPKD and that may
both participate in disease pathogenesis and serve as a target for therapeutic development. While it remains to
be established whether the newly-identified metabolic derangements that characterize ADPKD are direct drivers
of cyst formation, it is clear that the nature and activities of a cell's many and varied intertwined metabolic circuits
plays a central role in determining its capacity to invest the energy required in order to participate in the
proliferation and active solute and fluid transport that are required for cyst growth. The main goal of this proposal
is to provide the research community with novel tools and data sets that will substantially enhance efforts to
explore and exploit the metabolic changes that characterize ADPKD. We will produce a uniquely designed and
rigorously curated resource based upon novel in vivo models of the cell specific transcriptomic, mitochondrial
proteomic and mitochondrial metabolic effects that result from the earliest stages after loss of the PC proteins
and that are further informed by the effects of concomitant cilia loss and PC protein reactivation. This program
will make use of adult inducible conditional PC knockout mouse models and will employ strategies that will permit
conditional isolation of ribosomes (TRAP) and conditional isolation of mitochondria, thus enabling cell-type-
specific transcriptomic and mitochondrial proteomic and metabolomic studies. State of the art in vivo metabolic
flux studies will be applied to the kidney cortices of these novel genetic mouse models. The results of these
analyses will be combined to produce robust biological data sets that will be assembled through application of
the requisite informatics mechanisms in order to disseminate these data to the broader research community in
near real time. Critically, our in vivo studies are designed to discover the earliest changes that occur after kidney
tubules...

## Key facts

- **NIH application ID:** 10434820
- **Project number:** 5RC2DK120534-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Michael J. Caplan
- **Activity code:** RC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,289,362
- **Award type:** 5
- **Project period:** 2019-09-09 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434820

## Citation

> US National Institutes of Health, RePORTER application 10434820, In vivo Pathway Discovery in Autosomal Dominant Polycystic Kidney Disease (5RC2DK120534-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434820. Licensed CC0.

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