Ingraham, Holly - University of California, San Francisco - Department of Chemistry and Chemical Biology

研究领域

We are broadly interested in programs that regulate endocrine and neuroendocrine tissue development. Our research focuses on NR5A nuclear hormone receptors because of their critical roles in endocrine organogenesis and metabolism. After showing that phospholipids serve as NR5A ligands we found thsimilar to plasma membrane signaling by PIP2 and PIP3, nuclear PI3-kinases and -phosphatases are able to act on the exposed-bound phospholipid headgroup and modulate receptor activity, illustrating how this class of transcription factor could be used to decode nuclear lipid signaling. NR5A receptors are also regulated by sumoylation, and as such are ideal models for understanding how this PTM regulates gene expression. Our recent study established that SUMO-less SF-1 mice exhibit inappropriate activation of SUMO-sensitive genes involved in cell specification and proliferation. Using a gene-expression HTS, we have identified a drug that ablates NR5A sumoylation in cells. Such leads may prove useful for targeting metabolic diseases and cancers. We also study the development of a neuroendocrine center, the ventromedial hypothalamus (VMH), which controls metablism and reproduction. Using mouse genetics we mapped efferent projections from this regin, and have recently discovered that neurons in the VMHvl region control an estrogen-responsive female-specific circuit of physical activity.

近期论文

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Select item 25543145 An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. Correa SM, Newstrom DW, Warne JP, Flandin P, Cheung CC, Lin-Moore AT, Pierce AA, Xu AW, Rubenstein JL, Ingraham HA. Cell Rep. 2015 Jan 6;10(1):62-74. doi: 10.1016/j.celrep.2014.12.011. Epub 2014 Dec 24. PMID: 25543145 [PubMed - in process] Free Article Select item 25288771 The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1. Blind RD, Sablin EP, Kuchenbecker KM, Chiu HJ, Deacon AM, Das D, Fletterick RJ, Ingraham HA. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15054-9. doi: 10.1073/pnas.1416740111. Epub 2014 Oct 6. PMID: 25288771 [PubMed - in process] Free PMC Article Select item 22987798 Genetic labeling of steroidogenic factor-1 (SF-1) neurons in mice reveals ventromedial nucleus of the hypothalamus (VMH) circuitry beginning at neurogenesis and development of a separate non-SF-1 neuronal cluster in the ventrolateral VMH. Cheung CC, Kurrasch DM, Liang JK, Ingraham HA. J Comp Neurol. 2013 Apr 15;521(6):1268-88. doi: 10.1002/cne.23226. PMID: 22987798 [PubMed - indexed for MEDLINE] Free PMC Article Select item 22715467 Direct modification and activation of a nuclear receptor-PIP₂ complex by the inositol lipid kinase IPMK. Blind RD, Suzawa M, Ingraham HA. Sci Signal. 2012 Jun 19;5(229):ra44. doi: 10.1126/scisignal.2003111. PMID: 22715467 [PubMed - indexed for MEDLINE] Free PMC Article Select item 22641177 An affective disorder in zebrafish with mutation of the glucocorticoid receptor. Ziv L, Muto A, Schoonheim PJ, Meijsing SH, Strasser D, Ingraham HA, Schaaf MJ, Yamamoto KR, Baier H. Mol Psychiatry. 2013 Jun;18(6):681-91. doi: 10.1038/mp.2012.64. Epub 2012 May 29. PMID: 22641177 [PubMed - indexed for MEDLINE] Free PMC Article Select item 21820362 Eliminating SF-1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. Lee FY, Faivre EJ, Suzawa M, Lontok E, Ebert D, Cai F, Belsham DD, Ingraham HA. Dev Cell. 2011 Aug 16;21(2):315-27. doi: 10.1016/j.devcel.2011.06.028. Epub 2011 Aug 4. PMID: 21820362 [PubMed - indexed for MEDLINE] Free PMC Article Select item 21697939 Metabolism: A lipid for fat disorders. Ingraham HA. Nature. 2011 Jun 22;474(7352):455-6. doi: 10.1038/474455a. No abstract available. PMID: 21697939 [PubMed - indexed for MEDLINE] Select item 21419222 Demasculinization and feminization of male gonads by atrazine: consistent effects across vertebrate classes. Hayes TB, Anderson LL, Beasley VR, de Solla SR, Iguchi T, Ingraham H, Kestemont P, Kniewald J, Kniewald Z, Langlois VS, Luque EH, McCoy KA, Muñoz-de-Toro M, Oka T, Oliveira CA, Orton F, Ruby S, Suzawa M, Tavera-Mendoza LE, Trudeau VL, Victor-Costa AB, Willingham E. J Steroid Biochem Mol Biol. 2011 Oct;127(1-2):64-73. doi: 10.1016/j.jsbmb.2011.03.015. Epub 2011 Mar 23. Review. PMID: 21419222 [PubMed - indexed for MEDLINE] Free PMC Article Select item 21391689 Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2). Whitby RJ, Stec J, Blind RD, Dixon S, Leesnitzer LM, Orband-Miller LA, Williams SP, Willson TM, Xu R, Zuercher WJ, Cai F, Ingraham HA. J Med Chem. 2011 Apr 14;54(7):2266-81. doi: 10.1021/jm1014296. Epub 2011 Mar 10. PMID: 21391689 [PubMed - indexed for MEDLINE] Free PMC Article Select item 21068293 Molecular pathways controlling development of thalamus and hypothalamus: from neural specification to circuit formation. Blackshaw S, Scholpp S, Placzek M, Ingraham H, Simerly R, Shimogori T. J Neurosci. 2010 Nov 10;30(45):14925-30. doi: 10.1523/JNEUROSCI.4499-10.2010. Review. PMID: 21068293 [PubMed - indexed for MEDLINE] Free Article Select item 20889131 Regulation of C. elegans fat uptake and storage by acyl-CoA synthase-3 is dependent on NR5A family nuclear hormone receptor nhr-25. Mullaney BC, Blind RD, Lemieux GA, Perez CL, Elle IC, Faergeman NJ, Van Gilst MR, Ingraham HA, Ashrafi K. Cell Metab. 2010 Oct 6;12(4):398-410. doi: 10.1016/j.cmet.2010.08.013. PMID: 20889131 [PubMed - indexed for MEDLINE] Free PMC Article Select item 19549922 Stimulating the GPR30 estrogen receptor with a novel tamoxifen analogue activates SF-1 and promotes endometrial cell proliferation. Lin BC, Suzawa M, Blind RD, Tobias SC, Bulun SE, Scanlan TS, Ingraham HA. Cancer Res. 2009 Jul 1;69(13):5415-23. doi: 10.1158/0008-5472.CAN-08-1622. Epub 2009 Jun 23. PMID: 19549922 [PubMed - indexed for MEDLINE] Free PMC Article Select item 19549326 Neuroendocrine transcriptional programs adapt dynamically to the supply and demand for neuropeptides as revealed in NSF mutant zebrafish. Kurrasch DM, Nevin LM, Wong JS, Baier H, Ingraham HA. Neural Dev. 2009 Jun 23;4:22. doi: 10.1186/1749-8104-4-22. PMID: 19549326 [PubMed - indexed for MEDLINE] Free PMC Article Select item 19015525 The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1. Sablin EP, Woods A, Krylova IN, Hwang P, Ingraham HA, Fletterick RJ. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18390-5. doi: 10.1073/pnas.0808936105. Epub 2008 Nov 17. PMID: 19015525 [PubMed - indexed for MEDLINE] Free PMC Article Select item 18988706 Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA. Mol Endocrinol. 2009 Jan;23(1):25-34. doi: 10.1210/me.2007-0508. Epub 2008 Nov 6. PMID: 18988706 [PubMed - indexed for MEDLINE] Free PMC Article Select item 18838537 Decreased recognition of SUMO-sensitive target genes following modification of SF-1 (NR5A1). Campbell LA, Faivre EJ, Show MD, Ingraham JG, Flinders J, Gross JD, Ingraham HA. Mol Cell Biol. 2008 Dec;28(24):7476-86. doi: 10.1128/MCB.00103-08. Epub 2008 Oct 6. PMID: 18838537 [PubMed - indexed for MEDLINE] Free PMC Article Select item 18461179 The herbicide atrazine activates endocrine gene networks via non-steroidal NR5A nuclear receptors in fish and mammalian cells. Suzawa M, Ingraham HA. PLoS One. 2008 May 7;3(5):e2117. doi: 10.1371/journal.pone.0002117. PMID: 18461179 [PubMed - indexed for MEDLINE] Free PMC Article Select item 18077674 The neonatal ventromedial hypothalamus transcriptome reveals novel markers with spatially distinct patterning. Kurrasch DM, Cheung CC, Lee FY, Tran PV, Hata K, Ingraham HA. J Neurosci. 2007 Dec 12;27(50):13624-34. PMID: 18077674 [PubMed - indexed for MEDLINE] Free Article Select item 17132856 International Union of Pharmacology. LXVI. Orphan nuclear receptors. Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. Pharmacol Rev. 2006 Dec;58(4):798-836. Review. PMID: 17132856 [PubMed - indexed for MEDLINE] Free Article Select item 16917842 Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage. Tran PV, Akana SF, Malkovska I, Dallman MF, Parada LF, Ingraham HA. J Comp Neurol. 2006 Oct 10;498(5):637-48. PMID: 16917842 [PubMed - indexed for MEDLINE]