Biochemistry (Hall)Head of Research Unit Prof. Dr. Michael N. Hall, Prof. Dr.OverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 42 foundShow per page10 10 20 50 10007511 - HybridCrop: Process-oriented machine learning for robust crop modeling under climate extremes Research Project | 2 Project MembersImported from Grants Tool 4722429 Radiosensitization by RBM39 Depletion: Development of Novel Compounds for Cancer Treatment Research Project | 1 Project MembersImported from Grants Tool 4720500 The regulation of polyamide homeostasis in cancer Research Project | 2 Project MembersImported from Grants Tool 4708709 RBM39 arginine Research Project | 2 Project MembersImported from Grants Tool 4704397 Metabolic Reprogramming in Liver Cancer Research Project | 1 Project MembersImported from Grants Tool 4701414 PTES Research Project | 1 Project MembersImported from Grants Tool 4701181 Development of an MCT1/4 dual inhibitor as an anti-cancer drug Research Project | 2 Project MembersNo Description available Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice. Selective mTORC1 inhibitors to treat TSC Research Project | 3 Project MembersTuberous sclerosis complex (TSC) is a rare multisystem genetic disease caused by loss-of-function mutations in the tumor suppressor genes TSC1 or TSC2. As a consequence, the protein kinase mammalian target of rapamycin complex 1 (mTORC1) is constitutively active, which leads to uncontrolled cell growth. mTORC1 is thus a very attractive pharmacological target for the treatment of TSC. The clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives, termed rapalogs) is limited by their specificity, effectiveness, and safety. Chronic treatment with rapamycin/rapalogs is often associated with undesirable side effects on metabolism due to undesired mTORC2 inhibition. These side effects include high blood glucose, high blood lipids, and insulin resistance. We seek support i) to gain a deeper mechanistic understanding of mTORC1-TSC signaling pathways, ii) to continue developing an innovative anti-TSC strategy based on selective mTORC1 inhibition with a novel mechanism of action (rapamycin/rapalog unrelated), and iii) to perform in vivo (mouse) studies to gain insight into the translation of the in vitro data. The specific aims of this study are as follows: i) to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity in TSC1/2-deficient cell lines, ii) to identify optimized compounds that justify performing experiments in mice, iii) to determine if our optimized compounds selectively inhibit mTORC1 in wild type mice and in mice lacking TSC1 in the liver, and iv) to determine if our optimized compounds exhibit tumor reducing abilities in a mouse xenograft TSC model. This project may lead to a new generation of (rapamycin-rapalog unrelated) selective mTORC1 inhibitors and eventually to new treatment options for TSC as well as for other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of (non-selective) mTORC1 inhibitors. The clinical potential of these novel compounds would be immense and readily testable. We believe our approach could represent a paradigm shift, as we predict it to be more effective, more selective, and safer than the current standard of care in th selective mTORC1 inhibitors may greatly improve the health of TSC patients ii. Translation regulation in adipose tissue in obesity Research Project | 1 Project MembersChronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. We found that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in white adipose tissue (WAT). Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in the liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to a loss of HK2 by inhibiting the elongation of Hk2 mRNA translation. Thus, our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia. Here, we propose to investigate the mechanism of translational regulation of Hk2 mRNA in adipose tissue. 12345 1...5 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 42 foundShow per page10 10 20 50 10007511 - HybridCrop: Process-oriented machine learning for robust crop modeling under climate extremes Research Project | 2 Project MembersImported from Grants Tool 4722429 Radiosensitization by RBM39 Depletion: Development of Novel Compounds for Cancer Treatment Research Project | 1 Project MembersImported from Grants Tool 4720500 The regulation of polyamide homeostasis in cancer Research Project | 2 Project MembersImported from Grants Tool 4708709 RBM39 arginine Research Project | 2 Project MembersImported from Grants Tool 4704397 Metabolic Reprogramming in Liver Cancer Research Project | 1 Project MembersImported from Grants Tool 4701414 PTES Research Project | 1 Project MembersImported from Grants Tool 4701181 Development of an MCT1/4 dual inhibitor as an anti-cancer drug Research Project | 2 Project MembersNo Description available Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice. Selective mTORC1 inhibitors to treat TSC Research Project | 3 Project MembersTuberous sclerosis complex (TSC) is a rare multisystem genetic disease caused by loss-of-function mutations in the tumor suppressor genes TSC1 or TSC2. As a consequence, the protein kinase mammalian target of rapamycin complex 1 (mTORC1) is constitutively active, which leads to uncontrolled cell growth. mTORC1 is thus a very attractive pharmacological target for the treatment of TSC. The clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives, termed rapalogs) is limited by their specificity, effectiveness, and safety. Chronic treatment with rapamycin/rapalogs is often associated with undesirable side effects on metabolism due to undesired mTORC2 inhibition. These side effects include high blood glucose, high blood lipids, and insulin resistance. We seek support i) to gain a deeper mechanistic understanding of mTORC1-TSC signaling pathways, ii) to continue developing an innovative anti-TSC strategy based on selective mTORC1 inhibition with a novel mechanism of action (rapamycin/rapalog unrelated), and iii) to perform in vivo (mouse) studies to gain insight into the translation of the in vitro data. The specific aims of this study are as follows: i) to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity in TSC1/2-deficient cell lines, ii) to identify optimized compounds that justify performing experiments in mice, iii) to determine if our optimized compounds selectively inhibit mTORC1 in wild type mice and in mice lacking TSC1 in the liver, and iv) to determine if our optimized compounds exhibit tumor reducing abilities in a mouse xenograft TSC model. This project may lead to a new generation of (rapamycin-rapalog unrelated) selective mTORC1 inhibitors and eventually to new treatment options for TSC as well as for other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of (non-selective) mTORC1 inhibitors. The clinical potential of these novel compounds would be immense and readily testable. We believe our approach could represent a paradigm shift, as we predict it to be more effective, more selective, and safer than the current standard of care in th selective mTORC1 inhibitors may greatly improve the health of TSC patients ii. Translation regulation in adipose tissue in obesity Research Project | 1 Project MembersChronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. We found that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in white adipose tissue (WAT). Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in the liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to a loss of HK2 by inhibiting the elongation of Hk2 mRNA translation. Thus, our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia. Here, we propose to investigate the mechanism of translational regulation of Hk2 mRNA in adipose tissue. 12345 1...5
10007511 - HybridCrop: Process-oriented machine learning for robust crop modeling under climate extremes Research Project | 2 Project MembersImported from Grants Tool 4722429
Radiosensitization by RBM39 Depletion: Development of Novel Compounds for Cancer Treatment Research Project | 1 Project MembersImported from Grants Tool 4720500
The regulation of polyamide homeostasis in cancer Research Project | 2 Project MembersImported from Grants Tool 4708709
Metabolic Reprogramming in Liver Cancer Research Project | 1 Project MembersImported from Grants Tool 4701414
Development of an MCT1/4 dual inhibitor as an anti-cancer drug Research Project | 2 Project MembersNo Description available
Preclinical in vivo proof of mechanism study of selective mTORC1 inhibitors Research Project | 2 Project MembersLaufzeit 01.04.2022-31.01.2024 Increased activity of mammalian target of rapamycin complex 1(mTORC1) is linked to multiple disorders. We identified ten small compounds that selectively and efficiently inhibit mTORC1 in vitro with an innovative mode of action. We now aim to achieve precinlincal proof of mechanism in mice.
Selective mTORC1 inhibitors to treat TSC Research Project | 3 Project MembersTuberous sclerosis complex (TSC) is a rare multisystem genetic disease caused by loss-of-function mutations in the tumor suppressor genes TSC1 or TSC2. As a consequence, the protein kinase mammalian target of rapamycin complex 1 (mTORC1) is constitutively active, which leads to uncontrolled cell growth. mTORC1 is thus a very attractive pharmacological target for the treatment of TSC. The clinical applicability of the currently available mTORC1 inhibitors (rapamycin and its derivatives, termed rapalogs) is limited by their specificity, effectiveness, and safety. Chronic treatment with rapamycin/rapalogs is often associated with undesirable side effects on metabolism due to undesired mTORC2 inhibition. These side effects include high blood glucose, high blood lipids, and insulin resistance. We seek support i) to gain a deeper mechanistic understanding of mTORC1-TSC signaling pathways, ii) to continue developing an innovative anti-TSC strategy based on selective mTORC1 inhibition with a novel mechanism of action (rapamycin/rapalog unrelated), and iii) to perform in vivo (mouse) studies to gain insight into the translation of the in vitro data. The specific aims of this study are as follows: i) to determine the efficacy of selective mTORC1 inhibitors on mTORC1 activity in TSC1/2-deficient cell lines, ii) to identify optimized compounds that justify performing experiments in mice, iii) to determine if our optimized compounds selectively inhibit mTORC1 in wild type mice and in mice lacking TSC1 in the liver, and iv) to determine if our optimized compounds exhibit tumor reducing abilities in a mouse xenograft TSC model. This project may lead to a new generation of (rapamycin-rapalog unrelated) selective mTORC1 inhibitors and eventually to new treatment options for TSC as well as for other diseases characterized by mTORC1 hyperactivation that have not been addressable by the previous generations of (non-selective) mTORC1 inhibitors. The clinical potential of these novel compounds would be immense and readily testable. We believe our approach could represent a paradigm shift, as we predict it to be more effective, more selective, and safer than the current standard of care in th selective mTORC1 inhibitors may greatly improve the health of TSC patients ii.
Translation regulation in adipose tissue in obesity Research Project | 1 Project MembersChronically high blood glucose (hyperglycemia) leads to diabetes and fatty liver disease. Obesity is a major risk factor for hyperglycemia, but the underlying mechanism is unknown. We found that a high fat diet (HFD) in mice causes early loss of expression of the glycolytic enzyme Hexokinase 2 (HK2) specifically in white adipose tissue (WAT). Adipose-specific knockout of Hk2 caused enhanced gluconeogenesis and lipogenesis in the liver, a condition known as selective insulin resistance, leading to glucose intolerance. Furthermore, we observed reduced hexokinase activity in adipose tissue of obese and diabetic patients, and identified a loss-of-function mutation in the hk2 gene of naturally hyperglycemic Mexican cavefish. Mechanistically, HFD in mice led to a loss of HK2 by inhibiting the elongation of Hk2 mRNA translation. Thus, our findings identify adipose HK2 as a critical mediator of systemic glucose homeostasis, and suggest that obesity-induced loss of adipose HK2 is an evolutionarily conserved mechanism for the development of selective insulin resistance and thereby hyperglycemia. Here, we propose to investigate the mechanism of translational regulation of Hk2 mRNA in adipose tissue.
