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The primary focus of the Näär lab is to elucidate transcriptional and microRNA regulatory mechanisms governing cholesterol/lipid and metabolic homeostasis. Our studies over the last 20 years of the sterol- regulatory element-binding protein (SREBP) family of transcription factors, master regulators of cholesterol/lipid synthesis and trafficking, have led to an atomic-level understanding of the molecular mechanism of SREBP gene regulation. We have parlayed this detailed mechanistic knowledge to guide small molecule therapeutic targeting efforts resulting in the development of nanomolar inhibitors of the interaction of SREBPs with transcriptional co-activators. Ongoing NMR structure-guided medicinal chemistry efforts are aimed at further improving on these inhibitors, with the goal of identifying effective therapeutic modalities as treatments for diseases linked to abnormal cholesterol/lipids and metabolism, including many types of cancers, as well as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our work is innovative as it challenges the prevalent dogma that protein-protein interactions are not druggable.
Our studies have also identified microRNAs as crucial regulators of cholesterol/lipids and metabolism. We uncovered miR-33a/b as intronic microRNAs present in the SREBP genes that act in concert with the host genes to govern cholesterol/lipid homeostasis. Based on potent effects of antisense oligonucleotides (ASOs) targeting miR-33a/b on atherosclerosis in rodent models, we are currently pursuing state-of-the art locked nucleic acid (LNA) ASO technologies as novel and safe treatments for familial hypercholesterolemia and other cardiovascular diseases, as well as age-related macular degeneration (AMD).
Employing genome-wide association study data from >188,000 individuals we have identified a microRNA, miR-128-1, as a crucial regulator of circulating cholesterol and triglycerides. Surprisingly, miR-128- 1 is located in a genomic region on human chromosome 2 that is also strongly linked to recent positive selection, type 2 diabetes, and obesity. Based on our supportive in vivo data in several mouse obesity and metabolic disease models, we hypothesize that miR-128-1 represents a thrifty microRNA that acts as a potent negative regulator of energy expenditure, selected as a human evolutionary adaptation to promote fat storage to survive famine in ancient times. Currently, this represents a maladaptation in the developed world with abundant food, resulting in increased risk for cardio-metabolic diseases such as coronary artery disease, Metabolic Syndrome (MetS), obesity, type 2 diabetes, and non-alcoholic fatty liver diseases (NAFLD/NASH). Indeed, our ongoing and planned studies are aimed at developing LNA ASO modalities targeting miR-128-1 for the treatment of these metabolic diseases, and unpublished results from mouse obesity and NASH models look very promising. We have also unexpectedly found a link of miR-128-1 to Duchenne Muscular Dystrophy (DMD), a rare and early lethal muscle wasting disorder, and we are investigating a potential pathological disease modifying role of miR-128-1 in DMD, and whether it might represent a target for LNA ASOs as a novel DMD treatment in conjunction with other approaches such as exon-skipping ASO modalities.
Altogether, we are taking advantage of deep insights into molecular underpinnings of common and rare human diseases gained from our mechanistic studies to develop novel therapeutic targeting strategies.
The primary focus of the Näär lab is to elucidate transcriptional and microRNA regulatory mechanisms governing cholesterol/lipid and metabolic homeostasis. Our studies over the last 20 years of the sterol- regulatory element-binding protein (SREBP) family of transcription factors, master regulators of cholesterol/lipid synthesis and trafficking, have led to an atomic-level understanding of the molecular mechanism of SREBP gene regulation. We have parlayed this detailed mechanistic knowledge to guide small molecule therapeutic targeting efforts resulting in the development of nanomolar inhibitors of the interaction of SREBPs with transcriptional co-activators. Ongoing NMR structure-guided medicinal chemistry efforts are aimed at further improving on these inhibitors, with the goal of identifying effective therapeutic modalities as treatments for diseases linked to abnormal cholesterol/lipids and metabolism, including many types of cancers, as well as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our work is innovative as it challenges the prevalent dogma that protein-protein interactions are not druggable.
Our studies have also identified microRNAs as crucial regulators of cholesterol/lipids and metabolism. We uncovered miR-33a/b as intronic microRNAs present in the SREBP genes that act in concert with the host genes to govern cholesterol/lipid homeostasis. Based on potent effects of antisense oligonucleotides (ASOs) targeting miR-33a/b on atherosclerosis in rodent models, we are currently pursuing state-of-the art locked nucleic acid (LNA) ASO technologies as novel and safe treatments for familial hypercholesterolemia and other cardiovascular diseases, as well as age-related macular degeneration (AMD).
Employing genome-wide association study data from >188,000 individuals we have identified a microRNA, miR-128-1, as a crucial regulator of circulating cholesterol and triglycerides. Surprisingly, miR-128- 1 is located in a genomic region on human chromosome 2 that is also strongly linked to recent positive selection, type 2 diabetes, and obesity. Based on our supportive in vivo data in several mouse obesity and metabolic disease models, we hypothesize that miR-128-1 represents a thrifty microRNA that acts as a potent negative regulator of energy expenditure, selected as a human evolutionary adaptation to promote fat storage to survive famine in ancient times. Currently, this represents a maladaptation in the developed world with abundant food, resulting in increased risk for cardio-metabolic diseases such as coronary artery disease, Metabolic Syndrome (MetS), obesity, type 2 diabetes, and non-alcoholic fatty liver diseases (NAFLD/NASH). Indeed, our ongoing and planned studies are aimed at developing LNA ASO modalities targeting miR-128-1 for the treatment of these metabolic diseases, and unpublished results from mouse obesity and NASH models look very promising. We have also unexpectedly found a link of miR-128-1 to Duchenne Muscular Dystrophy (DMD), a rare and early lethal muscle wasting disorder, and we are investigating a potential pathological disease modifying role of miR-128-1 in DMD, and whether it might represent a target for LNA ASOs as a novel DMD treatment in conjunction with other approaches such as exon-skipping ASO modalities.
Altogether, we are taking advantage of deep insights into molecular underpinnings of common and rare human diseases gained from our mechanistic studies to develop novel therapeutic targeting strategies.
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论文共 75 篇作者统计合作学者相似作者
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Xin Hong,Whijae Roh,Ryan J. Sullivan,Keith H.K. Wong,Ben S. Wittner,Hongshan Guo,Taronish D. Dubash,Moshe Sade-Feldman,Benjamin Wesley,Elad Horwitz, Genevieve M. Boland,Dieuwke L. Marvin, Todd Bonesteel,Chenyue Lu, François Aguet,Risa Burr,Samuel S. Freeman,Laxmi Parida, Katherine Calhoun,Michelle K. Jewett, Linda T. Nieman,Nir Hacohen,Anders M. Näär,David T. Ting,Mehmet Toner,Shannon L. Stott,Gad Getz,Shyamala Maheswaran,Daniel A. Haber
openalex(2023)
Xin Hong,Whijae Roh,Ryan J. Sullivan,Keith H.K. Wong,Ben S. Wittner,Hongshan Guo,Taronish D. Dubash, Moshe Sade-Feldman,Benjamin Wesley,Elad Horwitz,Genevieve M. Boland,Dieuwke L. Marvin, Todd Bonesteel,Chenyue Lu,François Aguet,Risa Burr,Samuel S. Freeman,Laxmi Parida, Katherine Calhoun,Michelle K. Jewett,Linda T. Nieman,Nir Hacohen,Anders M. Näär,David T. Ting,Mehmet Toner,Shannon L. Stott,Gad Getz,Shyamala Maheswaran,Daniel A. Haber
crossref(2023)
Xin Hong,Whijae Roh,Ryan J. Sullivan,Keith H.K. Wong,Ben S. Wittner,Hongshan Guo,Taronish D. Dubash,Moshe Sade-Feldman,Benjamin Wesley,Elad Horwitz, Genevieve M. Boland,Dieuwke L. Marvin, Todd Bonesteel,Chenyue Lu, François Aguet,Risa Burr,Samuel S. Freeman,Laxmi Parida, Katherine Calhoun,Michelle K. Jewett, Linda T. Nieman,Nir Hacohen,Anders M. Näär,David T. Ting,Mehmet Toner,Shannon L. Stott,Gad Getz,Shyamala Maheswaran,Daniel A. Haber
crossref(2023)
Xin Hong,Whijae Roh,Ryan J. Sullivan,Keith H.K. Wong,Ben S. Wittner,Hongshan Guo,Taronish D. Dubash,Moshe Sade-Feldman,Benjamin Wesley,Elad Horwitz, Genevieve M. Boland,Dieuwke L. Marvin, Todd Bonesteel,Chenyue Lu, François Aguet,Risa Burr,Samuel S. Freeman,Laxmi Parida, Katherine Calhoun,Michelle K. Jewett, Linda T. Nieman,Nir Hacohen,Anders M. Näär,David T. Ting,Mehmet Toner,Shannon L. Stott,Gad Getz,Shyamala Maheswaran,Daniel A. Haber
openalex(2023)
Tammy C. T. Lan, Matty F. Allan,Lauren E. Malsick,Jia Z. Woo,Chi Zhu,Fengrui Zhang, Stuti Khandwala,Sherry S. Y. Nyeo,Yu Sun,Junjie U. Guo,Mark Bathe,Anders Näär,Anthony Griffiths,Silvi Rouskin
Chi Zhu,Justin Y. Lee,Jia Z. Woo,Lei Xu,Xammy Nguyenla,Livia H. Yamashiro,Fei Ji,Scott B. Biering,Erik Van Dis,Federico Gonzalez,Douglas Fox, Eddie Wehri,Arjun Rustagi,Benjamin A. Pinsky, Julia Schaletzky,Catherine A. Blish,Charles Chiu,Eva Harris,Ruslan I. Sadreyev,Sarah Stanley,Sakari Kauppinen,Silvi Rouskin,Anders M. Naar
Molecular Therapyno. 7 (2021): 2281-2293
Xin Hong,Whijae Roh,Ryan J. Sullivan,Keith H. K. Wong,Ben S. Wittner,Hongshan Guo,Taronish D. Dubash, Moshe Sade-Feldman,Benjamin Wesley,Elad Horwitz,Genevieve M. Boland,Dieuwke L. Marvin, Todd Bonesteel,Chenyue Lu,Francois Aguet,Risa Burr,Samuel S. Freeman,Laxmi Parida, Katherine Calhoun,Michelle K. Jewett,Linda T. Nieman,Nir Hacohen,Anders M. Naar,David T. Ting,Mehmet Toner,Shannon L. Stott,Gad Getz,Shyamala Maheswaran,Daniel A. Haber
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作者统计
#Papers: 75
#Citation: 11647
H-Index: 38
G-Index: 75
Sociability: 6
Diversity: 0
Activity: 0
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