Jonathan L. Tilly, PhD

Massachusetts General Hospital

Massachusetts General Hospital
Phone: (617) 724-2182
Fax: (617) 726-7548


jtilly@partners.org

Jonathan L. Tilly, PhD

Massachusetts General Hospital

EDUCATIONAL TITLES

  • Professor, Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School
  • Director, Vincent Center for Reproductive Biology, Massachusetts General Hospital

DF/HCC PROGRAM AFFILIATION

Research Abstract

My laboratory's primary research focus is to elucidate the biochemical and molecular biological events that are responsible for the induction of apoptosis (programmed cell death) in the mammalian ovary. We use a variety of approaches to map the ovarian cell death program, including gene expression analyses, gene knockout studies and transgenic mouse models. Our ultimate goal is to understand the mechanisms responsible for the induction of apoptosis in oocytes (the female germ cell), and how manipulation of cell death in the germ line impacts on ovarian lifespan and tumorigenesis (surface epithelial cell transformation). These studies may provide new clues as to the etiology of ovarian cancer in humans, as well as to the events that culminate in the normal menopause (ovarian senescence) and premature ovarian failure observed in female cancer patients post-therapy. Regarding the latter, with survival rates increasing in these patients, it is imperative that we discover new ways to provide a higher quality of life post-therapy through alleviation of one of the major side-effects of cancer therapy, that being premature menopause and infertility.

Publications

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  • Park ES, Woods DC, Tilly JL. Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling. Fertil Steril 2013; 100:1468-75. PubMed
  • Nehra D, Le HD, Fallon EM, Carlson SJ, Woods D, White YA, Pan AH, Guo L, Rodig SJ, Tilly JL, Rueda BR, Puder M. Prolonging the female reproductive lifespan and improving egg quality with dietary omega-3 fatty acids. Aging Cell 2012. PubMed
  • Woods DC, Telfer EE, Tilly JL. Oocyte family trees: old branches or new stems? PLoS Genet. 2012; 8:e1002848. PubMed
  • Zelinski MB, Murphy MK, Lawson MS, Jurisicova A, Pau KY, Toscano NP, Jacob DS, Fanton JK, Casper RF, Dertinger SD, Tilly JL. In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates. Fertil Steril 2011; 95:1440-1445.e7. PubMed
  • Wang N, Guo L, Rueda BR, Tilly JL. Cables1 protects p63 from proteasomal degradation to ensure deletion of cells after genotoxic stress. EMBO Rep. 2010; 11:633-9. PubMed
  • Gong SP, Lee ST, Lee EJ, Kim DY, Lee G, Chi SG, Ryu BK, Lee CH, Yum KE, Lee HJ, Han JY, Tilly JL, Lim JM. Embryonic stem cell-like cells established by culture of adult ovarian cells in mice. Fertil Steril 2010; 93:2594-601, 2601.e1-9. PubMed
  • Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, Bohr VA, Brosh RM, Brunet A, Depinho RA, Donehower LA, Finch CE, Finkel T, Gorospe M, Gudkov AV, Hall MN, Hekimi S, Helfand SL, Karlseder J, Kenyon C, Kroemer G, Longo V, Nussenzweig A, Osiewacz HD, Peeper DS, Rando TA, Rudolph KL, Sassone-Corsi P, Serrano M, Sharpless NE, Skulachev VP, Tilly JL, Tower J, Verdin E, Vijg J. Impact papers on aging in 2009. Aging (Albany NY) 2010; 2:111-21. PubMed
  • Wang N, Tilly JL. Epigenetic status determines germ cell meiotic commitment in embryonic and postnatal mammalian gonads. Cell Cycle 2010; 9:339-49. PubMed
  • Rueda BR, Tilly JL, Schorge JO. Surgical debulking before or after chemotherapy: stemming the tide on ovarian cancer recurrence. Onkologie 2010; 33:286-7. PubMed
  • Niikura Y, Niikura T, Tilly JL. Aged mouse ovaries possess rare premeiotic germ cells that can generate oocytes following transplantation into a young host environment. Aging (Albany NY) 2010; 1:971-8. PubMed
  • Tilly JL, Telfer EE. Purification of germline stem cells from adult mammalian ovaries: a step closer towards control of the female biological clock? 2009; 15:393-8. PubMed
  • Pru JK,Kaneko-Tarui T,Jurisicova A,Kashiwagi A,Selesniemi K,Tilly JL. Induction of proapoptotic gene expression and recruitment of p53 herald ovarian follicle loss caused by polycyclic aromatic hydrocarbons. Reprod Sci 2008; 16:347-56. PubMed
  • Selesniemi K,Lee HJ,Tilly JL. Moderate caloric restriction initiated in rodents during adulthood sustains function of the female reproductive axis into advanced chronological age. Aging Cell 2008; 7:622-9. PubMed
  • Tilly JL,Rueda BR. Minireview: stem cell contribution to ovarian development, function, and disease. Endocrinology 2008; 149:4307-11. PubMed
  • Lee HJ, Selesniemi K, Niikura Y, Niikura T, Klein R, Dombkowski DM, Tilly JL. Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol 2007; 25:3198-204. PubMed
  • Tilly JL, Johnson J. Recent arguments against germ cell renewal in the adult human ovary: is an absence of marker gene expression really acceptable evidence of an absence of oogenesis? Cell Cycle 2007; 6:879-83. PubMed
  • Perez GI, Acton BM, Jurisicova A, Perkins GA, White A, Brown J, Trbovich AM, Kim MR, Fissore R, Xu J, Ahmady A, D'Estaing SG, Li H, Kagawa W, Kurumizaka H, Yokoyama S, Okada H, Mak TW, Ellisman MH, Casper RF, Tilly JL. Genetic variance modifies apoptosis susceptibility in mature oocytes via alterations in DNA repair capacity and mitochondrial ultrastructure. Cell Death Differ 2006; 14:524-33. PubMed
  • Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428:145-50. PubMed
  • Takai Y, Canning J, Perez GI, Pru JK, Schlezinger JJ, Sherr DH, Kolesnick RN, Yuan J, Flavell RA, Korsmeyer SJ, Tilly JL. Bax, caspase-2, and caspase-3 are required for ovarian follicle loss caused by 4-vinylcyclohexene diepoxide exposure of female mice in vivo. Endocrinology 2002; 144:69-74. PubMed
  • Matikainen T, Perez GI, Jurisicova A, Pru JK, Schlezinger JJ, Ryu HY, Laine J, Sakai T, Korsmeyer SJ, Casper RF, Sherr DH, Tilly JL. Aromatic hydrocarbon receptor-driven Bax gene expression is required for premature ovarian failure caused by biohazardous environmental chemicals. Nat Genet 2001; 28:355-60. PubMed
  • Morita Y, Maravei DV, Bergeron L, Wang S, Perez GI, Tsutsumi O, Taketani Y, Asano M, Horai R, Korsmeyer SJ, Iwakura Y, Yuan J, Tilly JL. Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function. Cell Death Differ 2001; 8:614-20. PubMed
  • Morita Y, Tilly JL. Segregation of retinoic acid effects on fetal ovarian germ cell mitosis versus apoptosis by requirement for new macromolecular synthesis. Endocrinology 1999; 140:2696-703. PubMed
  • Morita Y, Perez GI, Maravei DV, Tilly KI, Tilly JL. Targeted expression of Bcl-2 in mouse oocytes inhibits ovarian follicle atresia and prevents spontaneous and chemotherapy-induced oocyte apoptosis in vitro. Mol Endocrinol 1999; 13:841-50. PubMed
  • Robles R, Tao XJ, Trbovich AM, Maravel DV, Nahum R, Perez GI, Tilly KI, Tilly JL. Localization, regulation and possible consequences of apoptotic protease-activating factor-1 (Apaf-1) expression in granulosa cells of the mouse ovary. Endocrinology 1999; 140:2641-4. PubMed
  • Perez GI, Tao XJ, Tilly JL. Fragmentation and death (a.k.a. apoptosis) of ovulated oocytes. Mol Hum Reprod 1999; 5:414-20. PubMed
  • Perez GI, Robles R, Knudson CM, Flaws JA, Korsmeyer SJ, Tilly JL. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat Genet 1999; 21:200-3. PubMed
  • Morita Y, Manganaro TF, Tao XJ, Martimbeau S, Donahoe PK, Tilly JL. Requirement for phosphatidylinositol-3'-kinase in cytokine-mediated germ cell survival during fetal oogenesis in the mouse. Endocrinology 1999; 140:941-9. PubMed
  • Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A, Varmuza S, Latham KE, Flaws JA, Salter JC, Hara H, Moskowitz MA, Li E, Greenberg A, Tilly JL, Yuan J. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 1998; 12:1304-14. PubMed
  • Kugu K, Ratts VS, Piquette GN, Tilly KI, Tao XJ, Martimbeau S, Aberdeen GW, Krajewski S, Reed JC, Pepe GJ, Albrecht ED, Tilly JL. Analysis of apoptosis and expression of bcl-2 gene family members in the human and baboon ovary. Cell Death Differ 1999; 5:67-76. PubMed
  • Trbovich AM, Hughes FM, Perez GI, Kugu K, Tilly KI, Cidlowski JA, Tilly JL. High and low molecular weight DNA cleavage in ovarian granulosa cells: characterization and protease modulation in intact cells and in cell-free nuclear autodigestion assays. Cell Death Differ 1999; 5:38-49. PubMed
  • Perez GI, Tilly JL. Cumulus cells are required for the increased apoptotic potential in oocytes of aged mice. Hum Reprod 1998; 12:2781-3. PubMed
  • Perez GI, Knudson CM, Leykin L, Korsmeyer SJ, Tilly JL. Apoptosis-associated signaling pathways are required for chemotherapy-mediated female germ cell destruction. Nat Med 1997; 3:1228-32. PubMed
  • Tilly JL. Apoptosis and the ovary: a fashionable trend or food for thought? Fertil Steril 1997; 67:226-8. PubMed
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