# BLR&D Research Career Scientist Award

> **NIH VA IK6** · VA LOMA LINDA HEALTHCARE SYSTEM · 2020 · —

## Abstract

The current research focus of the nominee is two-fold: The first is to delineate a unique molecular mechanism
regulating functional activity of osteoclasts that involves negative regulation of the expression of a distinctive
osteoclastic protein-tyrosine phosphatase (PTP-oc), which is a potent activator of functional activity of mature
osteoclasts, by microRNA-17 (miR17). This project is supported by a BLR&D Merit Review award and seeks to
test 3 hypotheses: 1) resorption cytokines activates osteoclasts via suppression of miR17 expression; 2)
conditional deletion of miR17 in osteoclasts increases PTP-oc expression, which in turn stimulates osteoclast
activity via up-regulation of the PTP-oc signaling; and 3) conditional overexpression of miR17 in osteoclasts
reduces PTP-oc expression and inhibits physiologically- and pathologically-induced bone resorption. It has
three Aims: Aim 1 tests the first hypothesis by determining if treatment with resorption modulators regulates the
promoter activity of miR17 in osteoclasts; demonstrating direct effects of resorption modulators on transcription
of the miR17~92 gene; and performing ChIP-seq analysis to identify key transcription factors. Aim 2 tests the
second hypothesis by characterizing the in vivo and in vitro bone and osteoclast phenotypes of osteoclast
miR17~92 conditional knockout mice, determining effects of miR17~92 deficiency on PTP-oc mRNA level, the
PTP-oc signaling, and resorption activity of osteoclasts, and determining whether re-introduction of miR17 into
miR17~92 deficient osteoclasts would “restore” the osteoclast phenotype; and evaluating effects of miR17~92
deficiency on osteoclast differentiation. Aim 3 tests the third hypothesis by generating transgenic mice with
conditional overexpression of miR17~92 in osteoclasts by crossing LysM-Cre mice with mice harboring the
miR17~92 transgene downstream to a loxP-flanked Neo-STOP cassette at the ROSA locus, determining the
effects of conditional overexpression of miR17~92 in osteoclasts on bone and osteoclast phenotypes, and if
overexpression of miR17~92 in osteoclasts would blunt the ovariectomy- and calcium depletion-induced bone
resorption. This work should yield insights into how mature osteoclast activity is regulated, which is important in
our overall understanding of the pathophysiology of various subtypes of osteoporosis and bone-wasting
diseases. It may also provide novel drug targets (e.g., miR17) for screening of small molecular compounds for
use to develop effective anti-resorption therapies for certain subtypes of osteoporosis. The second focus is to
develop an innovative EphA4-based small molecular therapeutic strategy to prevent and treat osteoarthritis
(OA) and posttraumatic OA (PTOA). This project is funded by a DoD Idea Development award. The rationale
of this project is based on the exciting discovery of an opposing regulatory effects of the forward signaling of
EphA4 on osteoclasts (inhibiting bone resorption) as opposed to...

## Key facts

- **NIH application ID:** 9898226
- **Project number:** 5IK6BX003782-04
- **Recipient organization:** VA LOMA LINDA HEALTHCARE SYSTEM
- **Principal Investigator:** Kin-Hing William Lau
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898226

## Citation

> US National Institutes of Health, RePORTER application 9898226, BLR&D Research Career Scientist Award (5IK6BX003782-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898226. Licensed CC0.

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