# Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $361,857

## Abstract

Project Summary/Abstract
 Metals such as copper and iron are essential metals in biology, as their redox activities facilitate basic cellular
processes ranging from antioxidant defense to respiration, along with emerging regulatory roles in cell signaling.
However, this redox activity can be detrimental when their homeostasis is disrupted, leading to oxidative stress
and damage associated with diseases spanning neurodegeneration, metabolic disorders, and cancer. The
context in which a metal resides within a biological environment significantly influences its activity and function.
Recent years have seen a rise in tools for monitoring metal ions and have illuminated the diversity in metal
speciation in biology, but many of these tools are focused on probing metals in the intracellular space. The state-
of-the-art methods for assessing metal status in extracellular fluids such as blood plasma focus either on absolute
quantitation or evaluate a limited number of metal-containing species. While these methods have offered
important insight into extreme cases of metal deficiency or overload, subtle imbalances are more challenging to
diagnose and understand with the available methods. The objective of this research program is to expand and
elucidate the metal speciation of the extracellular space, specifically in the blood plasma and the interstitial
space. In mapping the metals in blood plasma, our strategy focuses on determining the bioinorganic chemistry
of a dynamic population of biological molecules known as hormones. Hormones are the chemical messengers
of the body’s endocrine system that carries information from specialized glands to target tissues and organs to
maintain balance in response to internal and external stimuli. In an area that we term “metalloendocrinology”,
we seek to identify hormones that interact with metals in the plasma, determine how metals influence hormone
function or how hormones may regulate the levels of metals, and assess how these interactions impact
metabolism, energy consumption, daily biological rhythms, and nutritional health. Additionally, we seek to initiate
investigations into the relatively-unexplored inorganic biochemistry of the interstitial space, which contains the
fluid that bathes the organs. This milieu offers challenges in collection and isolation for ex vivo analysis, we thus
seek to develop imaging agents targeted to this extracellular locale that respond to specific metal ions of interest.
Using approaches inspired by chemical biology, biomedical engineering, and spectroscopy, we propose both
bioluminescent and peptide-based imaging platforms that are coupled to chemoselective reaction-based
strategies for probing interstitial metals. The insights and technologies that emerge from this proposal will directly
impact nutritional treatments, hormone therapy development, and biomarker discovery for metal status.

## Key facts

- **NIH application ID:** 10413201
- **Project number:** 5R35GM133684-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Marie C. Heffern
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,857
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10413201

## Citation

> US National Institutes of Health, RePORTER application 10413201, Metalloendocrinology: Mapping Bioinorganic Chemistry in the Extracellular Space (5R35GM133684-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10413201. Licensed CC0.

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