# Hormonal Control of Calcium Metabolism

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $2,054,112

## Abstract

Program Project "Hormonal Control of Calcium Metabolism" brings together a group of highly 
productive investigators who have worked closely together for a number of years supported by the 
project and other funded research grants. Tools of chemical molecular and cellular biology plus 
available carefully designed genetically modified animals are used to evaluate the role of 
parathyroid hormone in bone and renal cell biology. Several exciting medical translational 
applications have already come from this work and the potential for several more is evident. 
Project I (Gardella PI) Mechanisms of ligand binding and activation at the PTHR1 expands on earlier 
work that probes molecular details of ligand/receptor activation including newly available small 
molecule peptidomimetics as well as new chemical strategies to alter the pharmacokinetic and 
therefore ultimately pharmacodynamic of PTH analogs. Important translational implications from this 
work have been the discovery of a long-acting form of PTH for treatment of hypoparathyroidism soon 
to be entering phase 1 clinical trials and development of peptide negative agonists that show 
promise in animal models of controlling the multiple skeletal abnormalities seen in the hereditary 
disorder Jansen's disease. Project II (Kronenberg PI) PTH actions on cells of the osteoblast 
lineage builds on earlier progress with discovery of the first specific cellular target of PTH 
action the SIK kinases. This discovery opens a new field of important basic science investigation 
into the mode of action of PTH and has important translational implications in that the small 
molecule kinase inhibitors already discovered might ultimately lead to an orally active agent 
useful in the treatment of osteoporosis. Meantime these investigators continue to probe the effects 
of PTH on cellular targets of PTH action in bone from earliest precursors to mature osteoblasts and 
osteocytes. This work in addition to its fundamental interest could help with understanding how to 
improve PTH action since it is known that its effect wanes after continuous use for 12 months or 
less even though there are bone deficits remaining. Project III (Jueppner PI) renal regulation of 
phosphate homeostasis and its effects on bone deals with several recent novel findings. The first 
is importance of signal selectivity in PTH analogs in phosphate metabolism and bone cell maturation 
and secondly, the implications of high bone mass seen with skeletal transgenic expression of the 
Jansen's disease (JMC transgene) also studying a newly available specific inhibitor of NPT2A that 
may prove to be useful in hereditary disorders of hyperphosphatemia and CKD. Project IV (Mannstadt 
and Wein co-PI’s) The role of salt inducible kinases in renal PTH action builds on the recent 
discovery of the importance of the SIK kinase family in PTH bone action the investigators having 
demonstrated convincingly in preliminary work that SIK kinases are also critic...

## Key facts

- **NIH application ID:** 10434868
- **Project number:** 5P01DK011794-54
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** HENRY M. KRONENBERG
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,054,112
- **Award type:** 5
- **Project period:** 1997-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434868

## Citation

> US National Institutes of Health, RePORTER application 10434868, Hormonal Control of Calcium Metabolism (5P01DK011794-54). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10434868. Licensed CC0.

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