Long's NSBRI research project will focus on the causes and possible methods of treating or preventing bone loss resulting from the prolonged weightlessness of space travel.

The research also has great relevance for patients on Earth who are immobilized for long periods -- paraplegics, quadriplegics, and people in casts, says Long's mentor for the project, SFVAMC staff physician Daniel D. Bikle, MD, PhD, a professor of medicine and dermatology at UCSF.

As an NSBRI Fellow, Long will receive $40,000 per year for two years for his research at SFVAMC. In addition, as a member of an NSBRI science and technology team, he will collaborate in person and via teleconference with NSBRI colleagues. He and the other two Fellows were chosen from among a nationwide pool of applicants.

"The loss of mechanical forces on bone in the weightlessness of space dramatically weakens bone," says Long. "The ability of humans to conduct prolonged missions to the moon and Mars will require that the structural integrity of the skeleton be maintained."

Astronauts who spend weeks or months in the weightless environment of space -- a state called skeletal unloading -- lose bone because, in the absence of gravity, they lose the ability to make enough new bone cells to replace old cells that die in the normal course of bone metabolism. After their return to Earth's gravity, an event known as reloading, bone cell production can take months to return to normal. During that time, bones are highly vulnerable to fracture.

Here on Earth, explains Bikle, immobilized patients experience bone loss for the same reason astronauts do: their skeletons have not borne any weight. "This makes their rehabilitation risky, because, like astronauts who have returned to earth, they are predisposed to fractures."

Long's research project will focus on the relationship between three substances: insulin-like growth factor-1 (IGF-1), a chemical produced in bone and other organs that promotes the growth of bone and cartilage; IGF-1 receptor, which resides in bone cells and enables them to respond to IGF-1; and beta-3 integrin, a protein that among other roles promotes the function of IGF-1 receptor.

Long's and Bikle's hypothesis is that during prolonged weightlessness, beta-3 integrin production decreases, which in turn diminishes the function of IGF-1 receptor in bone. Without its receptor, IGF-1 has been shown by researchers to be ineffective. The result is a steep drop in the creation of new bone cells, leading to bone loss.

To investigate the hypothesis, Long will take a two-pronged research approach. In the first part, he will study a model of skeletal loading and unloading in human bone cell culture. In the second part, skeletally unloaded rats will be treated with IGF-1 and reloaded on a regular cycle -- much as astronauts might regularly engage in weight-bearing exercise while in orbit -- in order to stimulate integrin production and enhance or recover IGF-1 receptor function. The IGF-1 will act as a signaling device to allow Long to measure the strength of the interaction between integrins and IGF-1 receptor.

"Understanding this interaction, and the role it plays in how bones respond to mechanical forces, will allow interventions to protect the bones of astronauts," Long says.

"We hope to find that we can manipulate the IGF-1 system to accelerate rehabilitation, not only among astronauts but among a broad range of patients," says Bikle. "We might also learn how to prevent bone loss from taking place."

Long concludes, "I am excited and honored to contribute to our nation's efforts to safely explore space, the moon, and Mars."

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