Program Director/Principal Investigator (Last, First, Middle): Hrvatin, Sinisa Project Summary: Life on Earth has evolved fascinating adaptations such as torpor and hibernation to survive extreme environments. These extraordinary adaptations are characterized by profoundly decreased physiological functions, including metabolic rate, body temperature, circulation, breathing, and heart-rate. How warm-blooded animals enter, regulate, and survive these states remains one of the most fascinating mysteries of homeotherm biology, the understanding of which could have profound implications on human medicine. Investigating, for example, the mechanisms that adaptively modulate metabolism could provide new approaches to regulate human energy balance and treat metabolic diseases. An induced hypothermic and hypometabolic state could slow down disease progression, for example cancer growth. The pathways that enable cells and organs in torpor and hibernation to survive hypoxic and hypothermic stress might also be harnessed to facilitate cell survival during trauma, stroke, cardiac arrest, chemotherapy, or even neurodegeneration. Among the species naturally capable of entering these states are laboratory mice. Mice placed in environments devoid of food initiate torpor - a behavior characterized by bouts of greatly reduced core body temperature, movement, and metabolic rate, lasting several hours. Recently, employing novel transgenic tools and sequencing approaches, we examined this complex behavior and discovered that mouse torpor is regulated by a distinct population of neurons in the hypothalamus. Inhibiting these neurons prevents natural torpor and stimulating them rapidly decreases metabolic rate and body temperature, inducing a torpor-like state. This discovery forms the foundation for future explorations of mechanisms regulating torpor and hibernation, enabling for the first time genetic access to monitor, initiate, manipulate, and study these behaviors. In this proposal, we investigate key unanswered questions in the field of torpor and hibernation and explore potential applications for induced hibernation-like states in cancer biology. Specifically, we examine the neuronal circuit that regulates the decrease in body temperature and metabolic rate and explore the role of circulating factors in inducing this organism-wide state. We pioneer a new approach to induce a long-term hibernation-like state in mice, explore mammalian physiology in this state, and examine the impact of this state on cancer growth and protection from chemotherapy. Finally, we investigate the evolutionary conservation of torpor-regulating neurons across species including in non-human primates and human tissues and examine whether a torpor-like state can be induced in a non-human primate, paving the way to potential human applications. This proposal is bold and ambitious; however, each of the proposed projects contains clearly defined and feasible experiments whose results have the potential to greatly advance, if not transform, our understanding of torpor, hibernation, and homeotherm biology. The innovative and early-stage nature of this work, along with its potential to advance medical treatment, makes it ideally suited for the New Innovator Award.

Program Director/Principal Investigator (Last, First, Middle): Hrvatin, Sinisa Project Narrative: The mysteries of how animals enter and survive profoundly hypothermic and hypometabolic states like torpor and hibernation could transform medicine, from neonatal and critical care to cancer treatment and degenerative diseases. Our recent discovery of neurons that regulate torpor has enabled the induction of a hibernation-like state in mice and a novel way to study the fundamental mechanisms and potential applications of this state. This study aims to advance our understanding of how mice initiate and maintain a hypothermic and hypometabolic state, what the effects of this state are on physiology and cancer, and whether a similar state can be induced in primates, paving the way to potential human applications.