# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · BALTIMORE VA MEDICAL CENTER · 2020 · —

## Abstract

The skeleton is one of the most important structures in our bodies. Bones allow us to stand,
walk and move from one place to another, and they serve as protectors of our vital organs.
Degradation of our bones structure — osteoporosis — is a global health problem. The long-term
goal of my research is to understand the cellular and molecular mechanisms governing skeletal
development, homeostasis and repair. Currently, we are studying the coupling of bone cell
metabolic activity the role of sensory nerves in bone development and function.
 Studies supported by my Merit Review Award identified a novel pathway that links the
metabolic activity of skeletal osteoblasts to global fuel metabolism and energy expenditure. Insulin
receptor signaling in the osteoblast regulates the production and bioavailability of osteocalcin, which
in turn, acts in an endocrine fashion to regulate pancreatic insulin secretion and peripheral insulin
responsiveness. The existence of this bone-panaceas endocrine loop suggests that bone
consumes a significant proportion of the body’s overall fuel supply, and consequently is in
competition with other energy consuming tissues. Currently, we are studying mouse models with
genetic alterations that selectively attenuate either glucose or fatty acid metabolism. These models
will be used to determine the fuel requirements of bone accrual and determine the impact of energy
substrate oxidation and metabolism by osteoblasts on global energy flux during post-natal bone
development and in response to discrete anabolic episodes. The importance of these metabolic
pathways humans is profoundly illustrated by metabolic diseases such as diabetes and
osteoporosis caused by genetic or environmental disturbances in endocrine control mechanisms.
 In another project sponsored by NIH we are investigating the role of sensory nerves on bone
development and repair. Developing tissues dictate the amount and type of innervation they require
by secreting neurotrophins, which promote neuronal survival by activating distinct tyrosine kinase
receptors. We show that nerve growth factor (NGF) signaling through neurotrophic tyrosine kinase
receptor type 1 (TrkA) directs innervation of the developing mouse femur to promote vascularization
and osteoprogenitor lineage progression. At the start of primary ossification, TrkA-positive axons
penetrate perichondrial bone surfaces, coincident with NGF expression in cells adjacent to centers
of incipient ossification. Inactivation of TrkA signaling during embryogenesis in TrkA(F592A) mice
impaired innervation, delayed vascular invasion of the primary and secondary ossification centers,
decreased numbers of Osx-expressing osteoprogenitors, and decreased femoral length and volume.
These same phenotypic abnormalities were observed in mice following tamoxifen-induced disruption
of NGF in Col2-expressing perichondrial osteochondral progenitors. These findings indicate that
NGF serves as a skeletal neurotrophin to promote senso...

## Key facts

- **NIH application ID:** 9870202
- **Project number:** 1IK6BX004984-01
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** Thomas L Clemens
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870202

## Citation

> US National Institutes of Health, RePORTER application 9870202, BLR&D Research Career Scientist Award Application (1IK6BX004984-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870202. Licensed CC0.

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