# Mammalian circadian clock: genetics of PERIOD complex composition and structure.

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $589,823

## Abstract

Project Summary
 Circadian clocks are endogenous oscillators that drive daily rhythms of biological
processes. In mammals, circadian clocks are found in the brain and in most peripheral tissues.
Together, the distributed clocks constitute the fundamental timing system that coordinates daily
behavior, physiology, and metabolism.
 The mammalian clock is built from a transcriptional feedback loop that generates circadian
rhythms at the molecular level. The three PERIOD (PER) and two CRYPTOCHROME (CRY)
proteins, transcriptional autoregulatory proteins that are dedicated clock components, form a
large nuclear protein complex (PER complex) that lies at the heart of the feedback loop. In recent
years our laboratory has used preparative purification to analyze the constituent proteins of the
nuclear PER complex, providing new mechanistic insights into its transcriptional actions.
 In the present application we begin to address the question of how the nuclear PER
complex works in an integrated fashion as a macromolecular machine, a challenging but
essential next step in understanding. Building on our successful efforts, we propose to
characterize the properties, composition, and structural organization of PER complexes from
wildtype and mutant mice lacking individual PER or CRY proteins. By uniting preparative
purification of PER complexes with mouse genetics and structural biology, the application aims to
determine how each PER and CRY protein contributes to the assembly, composition, and three-
dimensional structure of the nuclear PER complex. If successful, the project offers to deepen our
knowledge of the clock mechanism substantially, possibly to an atomic level of resolution.
 Advances in understanding the mammalian circadian clock will have important implications
for our view of the genetic control of behavior and physiology, as well as for human health and
disease. Studies from mouse genetics, human genetics, and occupational health indicate that
defects of clock function lead to broad behavioral and metabolic dysfunction, producing, for
example, disrupted sleep-wake cycles, abnormal feeding, and a metabolic syndrome closely
resembling early-stage diabetes. If successful, the proposed study will provide new insights into
genetic and molecular mechanisms controlling fundamental behavioral and physiological
programs linked to major diseases.

## Key facts

- **NIH application ID:** 9955365
- **Project number:** 5R01NS095977-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** CHARLES J WEITZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $589,823
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955365

## Citation

> US National Institutes of Health, RePORTER application 9955365, Mammalian circadian clock: genetics of PERIOD complex composition and structure. (5R01NS095977-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9955365. Licensed CC0.

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