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Ryan Temel, PhD
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Ryan.Temel@uky.edu
(859) 218-1706
741 S Limestone, BBSRB B253, Lexington, KY 40536-0509
File Temel biosketch 072919.docx
Position(s): 
Associate Professor
Cardiovascular Research Center
Department of Physiology
Graduate Faculty in Nutritional Sciences
Affiliation(s): 
Cardiovascular Research Center
Physiology
Office of Biomedical Education
Other Affiliation(s): 
CVRC - Core Faculty
Nutritional Sciences Graduate Faculty
TRAC Committee
Interests / Specialties: 
Cardiovascular
Obesity & Diabetes
Bio / Education: 
  • Allegheny College, Meadville, PA, B.S., Chemistry, 1995
  • State University of NY at Stony Brook, Stony Brook, NY, Ph.D., Biochemistry & Molecular Biology, 2001
  • Wake Forest University, Winston-Salem, NC, Postdoc, Pathology/Lipid Sciences, 2001-2006
Research Description: 

Impact of biliary cholesterol secretion on atherosclerosis development

Excessive accumulation of cholesterol in the arteries drives atherosclerosis development.  Reverse cholesterol transport (RCT) is believed to regress or stabilize atherosclerotic lesions.  During RCT, cholesterol from atherosclerotic lesions is effluxed to high density lipoproteins (HDL), delivered to the liver, secreted into the bile, and excreted in feces.  We hypothesized that reduced biliary cholesterol secretion would increase the development of atherosclerosis due to a reduction in RCT.  Decreased biliary cholesterol secretion was achieved by hepatic overexpression of human NPC1L1 (L1Tg) and/or knockdown of hepatic ABCG5/G8 function using an ABCG8 antisense oligonucleotide (ASO). LDLR-/- and LDLR-/-/L1Tg mice received either control or ABCG8 ASO and were fed a high fat/low cholesterol diet for 20 weeks.  L1Tg mice and mice with hepatic ABCG8 knockdown had an >70% reduction in biliary cholesterol. The dramatic decrease in biliary cholesterol did not increase plasma cholesterol, and in fact mice with hepatic ABCG8 knockdown had reduced VLDL cholesterol and increased HDL cholesterol. Even more surprising, aortic atherosclerosis was significantly decreased in mice with compromised biliary cholesterol secretion. LDLR-/-/L1Tg treated with ABCG8 ASO had a >90% reduction in biliary cholesterol yet had ~70% less atherosclerosis compared to LDLR-/- controls.  Reducing biliary cholesterol did not result in major changes in macrophage RCT, hepatic cholesterol content, bile acid composition, and fecal excretion of neutral sterol.  Although the hepatic expression of FMO3 was significantly decreased in mice with reduced biliary cholesterol secretion, there was not a corresponding decrease in plasma TMAO, which is produced by FMO3 and has been linked to increased CVD risk.  In conclusion, reducing biliary cholesterol secretion paradoxically reduced atherosclerosis development through a mechanism that we are currently working to define.  Studies are also underway to determine whether reduced biliary cholesterol secretion limits atherosclerosis development in mice fed a high cholesterol diet.


Targeting microRNA-33 to reduce intracranial atherosclerosis and other neurovascular hallmarks of vascular cognitive impairment and dementia      

Intracranial atherosclerosis (ICAS) is a public health concern for both its role in stroke and as a contributing factor to vascular cognitive impairment and dementia (VCID). It is becoming widely accepted that poor vascular health facilitates poor brain health and that changes are needed to delay or prevent onset of VCID. Atherosclerotic vascular disease (AVD) is a chronic, maladaptive inflammatory disease that can affect extra- and intracranial arteries. The combination of lipoprotein retention, endothelial cell inflammation, myeloid infiltration, intracellular cholesterol accumulation, impaired apoptotic cell clearance, and extracellular matrix degradation leads to formation of advanced, unstable atherosclerotic plaques that can limit or occlude blood flow to tissues causing acute or chronic tissue damage.  ICAS often plays a causative role in ischemic stroke and subsequent cognitive decline.  ICAS has also been linked to both clinical signs of cognitive decline and Alzheimer’s disease pathology. Intracranial compared to extracranial atherosclerosis has a delayed onset of ~20 years but increases in prevalence and severity in individuals 60 years or older.  With the steady rise in the percentage of US citizens above the age of 60, ICAS will play an ever-growing role in the morbidity and mortality caused by VCID. Reducing low-density lipoprotein (LDL) concentration with statins is a primary therapeutic approach to stabilize AVD and attenuate ischemic event risk.  However, statins only reduce stroke risk by ~20% and do not appear to reduce VCID suggesting that treating hypercholesterolemia alone is not an ideal approach for decreasing VCID.  The obvious need for additional therapies that regress or stabilize ICAS has been hampered by the paucity of suitable animal models.  During an R01-funded study to determine the impact of microRNA-33 (miR-33) antagonism on cardiovascular AVD, we fortuitously discovered that our NHP model had ICAS and other neurovascular hallmarks of VCID.  We believe analysis of intracranial arteries and brains from our NHPs could have a high impact on the field of VCID research because of the potential discovery of a new therapy and animal model for VCID.  

Therapeutic targeting of metabolic microRNAs as a new treatment paradigm for NASH

Nonalcoholic steatohepatitis (NASH) is a progressive subtype of nonalcoholic fatty liver disease (NAFLD) characterized by the presence of steatosis, inflammation and fibrosis. NASH is strongly associated with obesity and the metabolic syndrome and is rapidly becoming the leading cause of end-stage liver disease, liver transplantation and hepatocellular carcinoma, underscoring the unmet medical need for effective and safe therapies for treatment of NASH. We have discovered two microRNAs (miRNAs) that function as key regulators of metabolic homeostasis. By employing GWAS meta-analysis we uncovered miR-128-1 as linked to circulating cholesterol and lipid abnormalities as well as to obesity and type 2 diabetes. Importantly, our data imply that miR-128-1 could be a promising therapeutic target for NASH, as pharmacologic inhibition of its function in high fat diet-induced obese (DIO) mice almost completely prevents hepatic lipid accumulation and inflammation. We have also identified miR-22 as another major regulator of metabolic homeostasis, which functions by orchestrating multiple pro-lipogenic programs that promote obesity. Notably, inhibition of miR-22 in DIO mice leads to loss of body weight and a decrease in hepatosteatosis and inflammation. Our goal is to identify antimiR compounds for effective and safe inhibition of miR-128-1 and miR-22 and assess their therapeutic potential to treat NASH in highly relevant mouse and non-human primate NASH models. Furthermore, we will evaluate hepatic and circulating miR-128-1 and miR-22 as biomarkers for NASH. We envision that the development of combined diagnostics and miRNA-targeted therapeutics based on dysregulation of miR-128-1 and miR-22 has high therapeutic potential, and if successfully translated to the clinic, will significantly impact public health worldwide.

 

Grants: 
Title: Therapeutic targeting of metabolic microRNAs as a new treatment paradigm for NASH
Principal Investigator: Sakari Kauppinen
Co-Investigator:  Ryan E. Temel
Agency:  Novo Nordisk Foundation
Grant No.: 33438       
Period: 1/1/2019– 12/31/2024
Major Goal of Research:  Identify antimiR compounds for effective and safe inhibition of miR-128-1 and miR-22 and assess their therapeutic potential to treat NASH in highly relevant mouse and non-human primate NASH models.

Title: Targeting microRNA-33 to reduce intracranial atherosclerosis and other neurovascular hallmarks of vascular cognitive impairment and dementia
Principal Investigator: Ryan E. Temel
Agency:  NIH, NINDS
Grant No.: R21 NS111979
Period: 04/01/2019 – 03/31/2021
Major Goal of Research: Determine whether miR-33 antagonism reduces intracranial atherosclerosis and other neurovascular pathologies associated with vascular cognitive impairment and dementia.

Title: Contributions of Hepatic and Intestinal Pathways to Cholesterol Excretion
Principal Investigator: Gregory Graf
Co-Investigator: Ryan E. Temel
Agency:  NIH, NIDDK
Grant No.: R01 DK113625
Period: 09/13/17 – 07/31/22
Major Goal of Research: Determine how transintestinal cholesterol elimination (TICE) is regulated by biliary cholesterol output, plasma lipoprotein donors, and an enterohepatic signaling axis involving bile acids.

Title: TRAF6 nanoimmunotherapy to resolve plaque inflammation  
Principal Investigator: Willem Mulder
Co-Investigator:  Ryan E. Temel
Agency:  NIH, NHLBI
Grant No.: R01 HL144072
Period: 7/1/2018– 06/30/2022
Major Goal of Research: Induce plaque regression with TRAF6i-HDL in a nonhuman primate atherosclerosis model.
Selected Publications: 
  1. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, Khatsenko OG, Kaimal V, Lees CJ, Fernandez-Hernando C, Fisher EA, Temel RE*, Moore KJ. Nature. 2011;478:404-7. PMCID: PMC3235584 (* equal contribution to study)
  2. The LXR-Idol Axis Differentially Regulates Plasma LDL Levels in Primates and Mice. Hong C, Marshall SM, McDaniel AL, Graham M, Layne JD, Cai L, Scotti E, Boyadjian R, Kim J, Chamberlain BT, Tangirala RK, Jung ME, Fong L, Lee R, Young SG, Temel RE*, Tontonoz. Cell Metab. 2014;20:910-918. (* co-corresponding author)
  3. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, Davies JP, Nilsson LM, Yu L. J Clin Invest. 2007;117:1968-78
  4. Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Temel RE, Sawyer JK, Yu L, Lord C, Degirolamo C, McDaniel A, Marshall S, Wang N, Shah R, Rudel LL, Brown JM. Cell Metab. 2010;12:96-102
PubMed Publications: 
  • Gnanaguru, G ; Wagschal, A ; Oh, J.; Saez-Torres, KL ; Li, T.; Temel, RE ; Kleinman, ME ; Näär, AM ; D'Amore, PA "Targeting of miR-33 ameliorates phenotypes linked to age-related macular degeneration." Molecular therapy : the journal of the American Society of Gene Therapy (2021): [PubMed Link] | [ Full text ]
  • Gatineau, E ; Arthur, G.; Poupeau, A ; Nichols, K ; Spear, BT ; Shelman, NR ; Graf, GA ; Temel, RE ; Yiannikouris, FB "The prorenin receptor and its soluble form contribute to lipid homeostasis." American journal of physiology. Endocrinology and metabolism 320, 3 (2021): E609-E618. [PubMed Link] |
  • Pathak, P ; Helsley, RN ; Brown, AL ; Buffa, JA ; Choucair, I ; Nemet, I ; Gogonea, CB ; Gogonea, V ; Wang, Z.; Garcia-Garcia, JC ; Cai, L.; Temel, R.; Sangwan, N ; Hazen, SL ; Brown, JM "Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism." American journal of physiology. Heart and circulatory physiology 318, 6 (2020): H1474-H1486. [PubMed Link] | [ Full text ]
  • Ito, M.; Ye, X.; Wang, Q.; Guo, L.; Hao, D.; Howatt, D.; Daugherty, A.; Cai, L.; Temel, R.; Li, XA "SR-BI (Scavenger Receptor BI), Not LDL (Low-Density Lipoprotein) Receptor, Mediates Adrenal Stress Response-Brief Report." Arteriosclerosis, thrombosis, and vascular biology 40, 8 (2020): 1830-1837. [PubMed Link] | [ Full text ]
  • Li, J.; Pijut, SS ; Wang, Y.; Ji, A.; Kaur, R.; Temel, RE ; Westhuyzen, DR ; Graf, GA "Simultaneous Determination of Biliary and Intestinal Cholesterol Secretion Reveals That CETP (Cholesteryl Ester Transfer Protein) Alters Elimination Route in Mice." Arteriosclerosis, thrombosis, and vascular biology 39, 10 (2019): 1986-1995. [PubMed Link] |
  • Kim, S.; Graham, MJ ; Lee, RG ; Yang, L.; Kim, S.; Subramanian, V.; Layne, JD ; Cai, L.; Temel, RE ; Shih, D ; Lusis, AJ ; Berliner, JA ; Lee, S. "Heparin-binding EGF-like growth factor (HB-EGF) antisense oligonucleotide protected against hyperlipidemia-associated atherosclerosis." Nutrition, metabolism, and cardiovascular diseases : NMCD 29, 3 (2019): 306-315. [PubMed Link] | [ Full text ]
  • Alsiraj, Y.; Chen, X.; Thatcher, SE ; Temel, RE ; Cai, L.; Blalock, E.; Katz, W ; Ali, HM ; Petriello, M ; Deng, P.; Morris, AJ ; Wang, X.; Lusis, AJ ; Arnold, AP ; Reue, K.; Thompson, K.; Tso, P.; Cassis, LA "XX sex chromosome complement promotes atherosclerosis in mice." Nature communications 10, 1 (2019): 2631. [PubMed Link] |
  • Hennessy, EJ ; Solingen, C.; Scacalossi, KR ; Ouimet, M.; Afonso, MS ; Prins, J ; Koelwyn, GJ ; Sharma, M.; Ramkhelawon, B.; Carpenter, S.; Busch, A.; Chernogubova, E ; Matic, LP ; Hedin, U.; Maegdefessel, L.; Caffrey, BE ; Hussein, MA ; Ricci, EP ; Temel, RE ; Garabedian, MJ ; Berger, JS ; Vickers, KC ; Kanke, M ; Sethupathy, P.; Teupser, D.; Holdt, LM ; Moore, KJ "The long noncoding RNA CHROME regulates cholesterol homeostasis in primate." Nature metabolism 1, 1 (2019): 98-110. [PubMed Link] | [ Full text ]
  • Hennessy, EJ ; Solingen, C.; Scacalossi, KR ; Ouimet, M.; Afonso, MS ; Prins, J ; Koelwyn, GJ ; Sharma, M.; Ramkhelawon, B.; Carpenter, S.; Busch, A.; Chernogubova, E ; Matic, LP ; Hedin, U.; Maegdefessel, L.; Caffrey, BE ; Hussein, MA ; Ricci, EP ; Temel, RE ; Garabedian, MJ ; Berger, JS ; Vickers, KC ; Kanke, M ; Sethupathy, P.; Teupser, D.; Holdt, LM ; Moore, KJ "The long noncoding RNA CHROME regulates cholesterol homeostasis in primates." Nature metabolism 1, 1 (2019): 98-110. [PubMed Link] | [ Full text ]
  • Coffey, AR ; Kanke, M ; Smallwood, TL ; Albright, J ; Pitman, W ; Gharaibeh, RZ ; Hua, K ; Gertz, E ; Biddinger, SB ; Temel, RE ; Pomp, D ; Sethupathy, P.; Bennett, BJ "microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO." Physiological genomics 51, 2 (2019): 59-71. [PubMed Link] | [ Full text ]
  • Lameijer, M ; Binderup, T.; van Leent, MMT ; Senders, ML ; Fay, F ; Malkus, J ; Sanchez-Gaytan, BL ; Teunissen, AJP ; Karakatsanis, N ; Robson, P ; Zhou, X.; Ye, Y.; Wojtkiewicz, G ; Tang, J.; Seijkens, TTP ; Kroon, J ; Stroes, ESG ; Kjaer, A ; Ochando, J ; Reiner, T ; Pérez-Medina, C ; Calcagno, C ; Fisher, EA ; Zhang, B.; Temel, RE ; Swirski, FK ; Nahrendorf, M ; Fayad, ZA ; Lutgens, E.; Mulder, WJM ; Duivenvoorden, R "Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates." Nature biomedical engineering 2, 5 (2018): 279-292. [PubMed Link] | [ Full text ]
  • Patel, SB ; Graf, GA ; Temel, RE "ABCG5 and ABCG8: more than a defense against xenosterols." Journal of lipid research 59, 7 (2018): 1103-1113. [PubMed Link] | [ Full text ]
  • Lameijer, M ; Binderup, T.; van Leent, MMT ; Senders, ML ; Fay, F ; Malkus, J ; Sanchez-Gaytan, BL ; Teunissen, AJP ; Karakatsanis, N ; Robson, P ; Zhou, X.; Ye, Y.; Wojtkiewicz, G ; Tang, J.; Seijkens, TTP ; Kroon, J ; Stroes, ESG ; Kjaer, A ; Ochando, J ; Reiner, T ; Pérez-Medina, C ; Calcagno, C ; Fisher, EA ; Zhang, B.; Temel, RE ; Swirski, FK ; Nahrendorf, M ; Fayad, ZA ; Lutgens, E.; Mulder, WJM ; Duivenvoorden, R "Author Correction: Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates." Nature biomedical engineering 2, 8 (2018): 623. [PubMed Link] | [ Full text ]
  • Zhang, L.; Rajbhandari, P.; Priest, C.; Sandhu, J.; Wu, X.; Temel, R.; Castrillo, A.; Aguiar Vallim, TQ ; Sallam, T.; Tontonoz, P. "Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP." eLife 6, (2017): [PubMed Link] | [ Full text ]
  • Brown, JM ; Temel, RE ; Graf, GA "Para-bile-osis Establishes a Role for Nonbiliary Macrophage to Feces Reverse Cholesterol Transport." Arteriosclerosis, thrombosis, and vascular biology 37, 5 (2017): 738-739. [PubMed Link] | [ Full text ]
  • Cheng, HS ; Besla, R.; Li, A.; Chen, Z.; Shikatani, EA ; Nazari-Jahantigh, M.; Hammoutène, A.; Nguyen, MA ; Geoffrion, M.; Cai, L.; Khyzha, N.; Li, T.; MacParland, SA ; Husain, M.; Cybulsky, MI ; Boulanger, CM ; Temel, RE ; Schober, A.; Rayner, KJ ; Robbins, CS ; Fish, JE "Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a." Circulation research 121, 4 (2017): 354-367. [PubMed Link] | [ Full text ]
  • Kim, S.; Yang, L.; Kim, S.; Lee, RG ; Graham, MJ ; Berliner, JA ; Lusis, AJ ; Cai, L.; Temel, RE ; Rateri, DL ; Lee, S. "Targeting hepatic heparin-binding EGF-like growth factor (HB-EGF) induces anti-hyperlipidemia leading to reduction of angiotensin II-induced aneurysm development." PloS one 12, 8 (2017): e0182566. [PubMed Link] | [ Full text ]
  • Ouimet, M.; Hennessy, EJ ; Solingen, C.; Koelwyn, GJ ; Hussein, MA ; Ramkhelawon, B.; Rayner, KJ ; Temel, RE ; Perisic, L.; Hedin, U.; Maegdefessel, L.; Garabedian, MJ ; Holdt, LM ; Teupser, D.; Moore, KJ "miRNA Targeting of Oxysterol-Binding Protein-Like 6 Regulates Cholesterol Trafficking and Efflux." Arteriosclerosis, thrombosis, and vascular biology 36, 5 (2016): 942-951. [PubMed Link] | [ Full text ]

Lab Information

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Lei Cai

Peter Hecker

Yipeng Sui

April Davis

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