# Molecular genetic bases of polycystic and tubulointerstitial kidney diseases > **NIH NIH K08** · YALE UNIVERSITY · 2023 · $167,940 ## Abstract Project Summary/Abstract Dr. Whitney Besse is a board-certified academic nephrologist with long-standing research interest in genetics whose goal is to become a physician scientist and make significant contributions to the study and treatment of genetic kidney diseases. The most common genetic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), is typically caused by mutations in the PKD1 or PKD2 genes, encoding polycystin-1 (PC1) and polycystin-2. Dr. Besse seeks to better understand the function of PC1 by identifying and describing the role of genes essential to this function. She has identified mutations in genes encoding proteins in the endoplasmic reticulum (ER) that also cause indistinguishable kidney/liver cysts but in the absence of PKD1 or PKD2 mutations. The mentor's laboratory defined in mouse models for these ER genes that kidney/liver cysts form due to insufficient PC1 functional dosage. This proposal will advance these studies by expanding genetic analysis methods/modalities and expanding a cohort of genetically unresolved cases of dominantly inherited polycystic kidney and liver disease (PKD/PLD) to define novel candidate disease genes. The study has identified five promising ER-associated candidate genes in this manner and a sixth gene has been experimentally validated in preliminary studies. The five new candidates will be systematically assessed by evaluating PC1 biogenesis, trafficking and cilia expression in CRISPR/Cas9-generated cell lines. Large precision medicine databases with exome sequences linked to clinical data will also be queried with the candidate genes to evaluate clinical variation and penetrance of phenotypes. Preliminary studies in this proposal identified mutations in DNAJB11, encoding an ER HSP40 chaperone as causing PKD/PLD due to impaired PC1 function. Patients with DNAJB11 mutations have also been reported to develop tubulointerstitial kidney disease. DNAJB11 is one of several proteins causing PKD/PLD that also associate with the ER protein translocation pore (translocon). This proposal will examine the protein interacting relationships among these several translocon associated polycystic disease gene products. We will explore the effects of DNAJB11 specifically on PC1 functional properties, on activation of the UPR, and its effect on trafficking of pathogenic missense variants of PC1. We will also investigate animal and cell models of tubulointerstitial kidney disease based on combined inactivation of polycystic and UPR genes to better resolve our understanding of how human mutations in these genes can result in both PKD/PLD and tubulointerstitial chronic kidney disease. Dr. Besse's training will include formal study, directed education by expert mentor/advisors, participation in seminars/meetings, and use of the proposed new methodologic approaches to create scientific contributions. This training, coupled with the extensive expertise and resources at Yale such as exome sequencing, stud... ## Key facts - **NIH application ID:** 10597658 - **Project number:** 5K08DK119642-05 - **Recipient organization:** YALE UNIVERSITY - **Principal Investigator:** Whitney Elise Besse - **Activity code:** K08 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $167,940 - **Award type:** 5 - **Project period:** 2019-06-01 → 2024-10-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10597658 ## Citation > US National Institutes of Health, RePORTER application 10597658, Molecular genetic bases of polycystic and tubulointerstitial kidney diseases (5K08DK119642-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10597658. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*