# Project 2:  The role of the HSP47/FKBP65 chaperone complex in osteogenesis imperfecta

> **NIH NIH P01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $417,417

## Abstract

Project 2 Summary
 
Genetic studies from our group has shown that mutations in the genes encoding either of two type I procollagen
chaperones, FKBP10 (which encodes the FKBP65 protein) or SERPINH1 (which encodes HSP47), produce
severe, recessively inherited forms of OI. Furthermore, we have determined that the two proteins form a complex
acting on type I procollagen trimers in the endoplasmic reticulum (ER) and whose function is essential for normal
type I procollagen biogenesis. Abrogation of the complex function leads to an altered cellular phenotype with
dilated ER, aggregates of intracellular type I procollagen, sequestering of chaperone complex components and
abnormal PLOD2-dependent cross-linking. Through the use of mutant FKBP65 and HSP47 cell lines, we have
established that PLOD2 is also a member of this newly identified chaperone complex and identifies chaperone
dysfunction as a new mechanism of disease in OI. These studies will primarily use newly generated mouse
models, complemented by studies in human OI tissues to establish a currently unappreciated mechanistic
paradigm for type I procollagen synthesis and a detailed understanding of how OI results from defects in this
process. This is a paradigm shift in our understanding of type I procollagen synthesis from the viewpoint of how
LH2 modifies or has access to type I procollagen and provides insight into how OI with contractures, also known
as Bruck syndrome, can result from mutations in either FKBP10 or PLOD2. The proposed experiments are
significant because they have the potential to have an extensive impact on our understanding of the role of
telopeptide cross-linking plays in the generation of a functional extracellular matrix and will be essential to
understanding and tailoring therapeutics in the context of altered bone matrix on downstream function of bone
and associated tissues.

## Key facts

- **NIH application ID:** 9974354
- **Project number:** 5P01HD070394-10
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Deborah Krakow
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,417
- **Award type:** 5
- **Project period:** — → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974354

## Citation

> US National Institutes of Health, RePORTER application 9974354, Project 2:  The role of the HSP47/FKBP65 chaperone complex in osteogenesis imperfecta (5P01HD070394-10). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9974354. Licensed CC0.

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