# Pathogenesis of Novel Forms of Osteogenesis Imperfecta

> **NIH NIH P01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $1,412,624

## Abstract

Overview Project Summary
 Osteogenesis Imperfecta (OI) is one of the most common heritable disorders of connective tissue. It is
characterized by brittle bones, and over the past four decades, the genetics of OI has taught us about the
basic mechanisms of procollagen assembly, post-translational modification, secretion, fibril formation and
matrix mineralization. In an accelerated phase of discovery over the past 9 years, the identification of new OI
genes has further informed us about the determinants of bone quantity and quality during skeletal development
and homeostasis. This Program Project Grant (PPG) began in 2010 and has significantly contributed to this
rapidly evolving field. In 2006, we reported that mutations in CRTAP caused recessive forms of severe OI
(types III and VII). CRTAP is part of a trimeric protein complex including P3H1 and CYB that together are
required for prolyl-3-hydroxylation, a poorly understood post-translational modification of clade A fibrillar
collagens (e.g., types I, II, and V collagen). We also identified additional type I procollagen binding proteins,
FKBP10 and HSP47, as important components in procollagen assembly and trafficking. We and others have
since discovered that mutations in the genes encoding these proteins also contribute to the expanding group of
brittle bone disorders (BBDs). The overall goal of this PPG is to elucidate the mechanistic consequences of
mutations in procollagen and its modification proteins on bone and to translate this into new targeted
diagnostic and therapeutic approaches. In this PPG renewal application, we hypothesize that the brittle bone
phenotype in OI is a developmental model of abnormal bone quality and quantity that broadly integrates 1)
altered matrix-to-cell signaling defects leading to abnormal bone quantity and cellular function, with 2) altered
strength, biochemical nature and intermolecular placement of collagen crosslinks leading to abnormal bone
mineralization and quality. To test this hypothesis, we will combine mouse genetic modeling, cell based
studies, state-of-the-art mass spectrometric analysis of collagen with continued human genetic gene discovery
to elucidate basic mechanisms that will inform genotype-based therapy and diagnostic biomarkers. The PPG
will leverage infrastructure housed within the Co-Investigators' programs. The PPG is composed of three
projects, a Functional Genomics Core, and an Administrative Core. The projects will answer three important
questions. Project 1: What are the downstream mechanisms in WNT1 forms of OI and how do mutations
affect osteoblast, osteoclast, osteocyte, and matrix function? Project 2: How do mutations in the
FKBP65/HSP47 & PLOD2 collagen chaperone complex affect bone development? Project 3: What are the
phenotypic and clinical consequences of altered crosslinking in OI patients and mice with defects affecting
procollagen modification and trafficking with regard to bone?

## Key facts

- **NIH application ID:** 9974347
- **Project number:** 5P01HD070394-10
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Brendan Lee
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,412,624
- **Award type:** 5
- **Project period:** 2011-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974347

## Citation

> US National Institutes of Health, RePORTER application 9974347, Pathogenesis of Novel Forms of Osteogenesis Imperfecta (5P01HD070394-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9974347. Licensed CC0.

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