David M. Sabatini

David M. Sabatini
Born (1968-01-27) January 27, 1968
New York, United States
Residence Cambridge, Massachusetts
Citizenship United States
Nationality American
Fields Biochemistry
Cell Biology
Systems Biology
Institutions Whitehead Institute
Massachusetts Institute of Technology
Broad Institute
Alma mater Brown University
Johns Hopkins School of Medicine
Doctoral advisor Solomon Snyder
Known for mammalian target of rapamycin
FK506 binding protein 12-rapamycin associated protein 1
Rictor
Raptor
Notable awards National Academy of Sciences

David M Sabatini is an American cell biologist and biochemist and a professor at the Whitehead Institute and the Massachusetts Institute of Technology, in Boston, Massachusetts. Among his research contributions are the discovery and study of the protein mTOR, now known to be important to understanding cancer and diabetes mellitus.

Biography

David M. Sabatini was born and raised in Westchester, New York to Dr. David D. Sabatini and Dr. Zulema Sabatini, both Argentine immigrants from Buenos Aires. He obtained both his MD and his Ph.D. at Johns Hopkins School of Medicine in Baltimore, Maryland, where he worked with Solomon Snyder on the discovery of mTOR and mTOR kinetics. Following his graduation, he was appointed a Whitehead Fellow in 1997. In 2002 Sabatini became assistant professor at the Whitehead Institute and at MIT, being promoted to tenured professor in 2006. He was elected to the National Academy of Sciences in 2016, joining his father, David D. Sabatini, Professor at New York University.[1]

Sabatini currently resides in Cambridge, Massachusetts. He is an avid biker and racket ball player. His younger brother, Bernardo L. Sabatini is a professor and neuroscientist at Harvard University.

Research

Discovery of mTOR

David Sabatini discovered mTOR while as a graduate student at Johns Hopkins University. mTOR is considered to be the mammalian target of rapamycin. Rapamycin was discovered in a soil sample from Easter Island in the 1970s.[2] Researchers studied this sample and found that the bacterium Streptomyces hygroscopicus made an antifungal, which they named rapamycin after the island's name Rapa Nui, which it was called by the locals meaning "navel of the world."[3] Studies on rapamycin revealed that it was a powerful antifungal agent that could arrest fungal activity at the G1 phase of the cell cycle. It was then tested in rats as a potential antifungal drug in humans, and was found to also greatly suppress their immune system by blocking the G1 to S phase transition in T-lymphocytes.[4] This has led to its clinical use as an immunosuppressant following organ transplantation.[5]

In 1991, a genetic screen was performed on Saccharomyces cerevisiae to elucidate what rapamycin was specifically targeting to initiate this response. It was found that knockout of three genes allowed for the fungus' resistance to rapamycin.[6] Two of the genes were called targets of rapamycin, or TOR, while the third gene was already characterized to be Fpr1, which is now known to be the yeast ortholog to FKBP12 binding protein in the TOR complexes.[7] In 1994, the mammalian target of rapamycin (mTOR) was identified as the rapamycin target in mammals.[8]

Function

mTOR integrates the input from upstream pathways, including insulin, growth factors (such as IGF-1 and IGF-2), and amino acids. mTOR also senses cellular nutrient, oxygen, and energy levels.[9] The mTOR pathway is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.[10] Rapamycin is a bacterial product that can inhibit mTOR by associating with its intracellular receptor FKBP12.[11][12] The FKBP12-rapamycin complex binds directly to the FKBP12-Rapamycin Binding (FRB) domain of mTOR, inhibiting its activity.[12]

mTOR stands for mammalian Target Of Rapamycin and was named based on the precedent that TOR was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits the cellular functions of Tor1 and Tor2.

Physiological significance (KO phenotypes)

The mTORC2 signaling pathway is less clearly defined than the mTORC1 signaling pathway. Therefore, performing knockout experiments is a good way to shed light on more specific molecules and their roles in this pathway. Protein function inhibition using knockdowns and knockouts were found to produce the following phenotypes:

Clinical significance

Aging

mTOR signaling pathway.

Decreased TOR activity has been found to slow aging in S. cerevisiae, C. elegans, and D. melanogaster.[26][27][28][29] The mTOR inhibitor rapamycin has been confirmed to increase lifespan in mice by independent groups at the Jackson Laboratory, University of Texas Health Science Center, and the University of Michigan.[30]

It is hypothesized that some dietary regimes, like caloric restriction and methionine restriction, cause lifespan extension by decreasing mTOR activity.[26][27] But infusion of leucine into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.[31]

mTOR inhibitors as therapies


David Sabatini has been involved in the development and testing of several mTOR inhibitors. MTOR inhibitors, e.g. rapamycin, are already used to prevent transplant rejection. Rapamycin is also related to the therapy of glycogen storage disease (GSD). Some articles reported that rapamycin can inhibit mTORC1 so that the phosphorylation of GS(glycogen synthase) can be increased in skeletal muscle. This discovery represents a potential novel therapeutic approach for glycogen storage diseases that involve glycogen accumulation in muscle. Various natural compounds, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit mTOR when applied to isolated cells in culture;[10][32] however, there is as yet no evidence that these substances inhibit mTOR when taken as dietary supplements.

Some (e.g. temsirolimus, everolimus) are beginning to be used in the treatment of cancer.[33][34] mTOR inhibitors may also be useful for treating several age-associated diseases.[35] Ridaforolimus is another mTOR inhibitor, currently in clinical development.

David Sabatini is the Scientific Founder of Navitor, a biotechnology company focused on mTORC1 inhibition as a disease therapy.[36]

Interactions

Mammalian target of rapamycin has been shown to interact with:[37]

See also

References

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