New Approaches to Reduce Residual Cardiovascular Risk

降低残余心血管风险的新方法

基本信息

  • 批准号:
    10543864
  • 负责人:
  • 金额:
    $ 248.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-01 至 2026-12-31
  • 项目状态:
    未结题

项目摘要

PPG Title: New Approaches to Reduce Residual Cardiovascular Risk SUMMARY/ABSTRACT In the last 40 years, significant progress has been made in reducing cardiovascular events by lowering plasma LDL-cholesterol (LDL-C). While statins and PCSK9 inhibitors effectively decrease LDL-C levels, significant residual risk of CHD remains even in maximally treated individuals with low plasma levels of LDL-C. Epidemiological and genetic studies suggest that a significant proportion of the residual risk is due to elevated plasma levels of triglyceride-rich ApoB-Containing Lipoproteins (ApoBCLs). The three projects that comprise this Program Project Grant (PPG) will elucidate new molecular mechanisms that regulate the synthesis, secretion, and metabolism of ApoBCLs. Our PPG is comprised of distinguished investigators with a longstanding history of collaboration, five of whom (Goldstein, Brown, Hobbs, Horton, and Cohen) have worked together for 25 years. In Project 1 of this new PPG, Radhakrishnan, Brown, and Goldstein have used an original and innovative screening protocol to identify a cholesterol-mimetic small molecule that binds to Scap with high specificity and blocks activation of SREBPs, the transcription factors that activate genes required for the synthesis of cholesterol, fatty acids (FAs), and triglycerides (TGs). This compound will be used to elucidate the molecular mechanism by which Scap senses sterols, enabling the first description of Scap’s cholesterol binding site at atomic resolution. The current cholesterol mimetic compound and more potent derivatives in development will be used to assess the clinical implications of a Scap inhibitor for reduction of plasma ApoBCLs. In Project 2, Horton, Kim, and Liang have identified a new lipogenic enzyme complex in liver. They will characterize components of the FA synthesis complex and determine how this complex interacts with additional FA modifying proteins and acyl-transferases required to synthesize TGs and ApoBCLs. Completion of the proposed studies will identify new opportunities for therapeutic interventions to reduce the synthesis of FAs, TGs, and VLDL. In Project 3, Hobbs and Cohen used population-based resequencing to identify loss-of-function mutations in angiopoietin-like (ANGPTL) 3 and 8. They showed that mutations in either protein result in lower plasma LDL- cholesterol and TG levels. Their studies will elucidate the mechanisms underlying the ApoBCL lowering effects of ANGPTL3 and ANGPTL8. In the process, they will define a new pathway that promotes clearance of ApoBCLs independently of the LDL receptor. The Research Projects will be supported by three Cores: Administrative, Tissue Culture & Antibody Production, and Mass Spectrometry. Members of this PPG have a long record of collaborative interactions and exceptional productivity. We will continue to focus on bold hypotheses designed to answer critical questions. The investigators take special pride in publishing papers that are characterized by originality and scientific rigor. The successful completion of our projects holds great promise for exposing new therapeutic opportunities for the reduction of plasma ApoBCLs and residual cardiovascular risk.
PPG标题:降低剩余心血管风险的新方法

项目成果

期刊论文数量(0)
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专利数量(0)

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JAY D. HORTON其他文献

JAY D. HORTON的其他文献

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{{ truncateString('JAY D. HORTON', 18)}}的其他基金

Administrative Core
行政核心
  • 批准号:
    10543865
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
Role of Multi-enzyme Complex in ApoBCL Secretion
多酶复合物在 ApoBCL 分泌中的作用
  • 批准号:
    10543873
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
Role of Multi-enzyme Complex in ApoBCL Secretion
多酶复合物在 ApoBCL 分泌中的作用
  • 批准号:
    10332597
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10657775
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10512732
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
UT Southwestern NORC
UT 西南 NORC
  • 批准号:
    10657774
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
New Approaches to Reduce Residual Cardiovascular Risk
降低残余心血管风险的新方法
  • 批准号:
    10332592
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10332593
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
UT Southwestern NORC
UT 西南 NORC
  • 批准号:
    10512731
  • 财政年份:
    2022
  • 资助金额:
    $ 248.46万
  • 项目类别:
TASK FORCE FOR OBESITY RESEARCH AT SOUTHWESTERN
西南肥胖研究工作组
  • 批准号:
    8363907
  • 财政年份:
    2011
  • 资助金额:
    $ 248.46万
  • 项目类别:

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乙酰辅酶A羧化酶在炎症代谢控制中的作用
  • 批准号:
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  • 批准号:
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  • 财政年份:
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肝脏特异性乙酰辅酶A羧化酶抑制对肝脏脂肪变性和胰岛素抵抗的影响
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  • 财政年份:
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肝乙酰辅酶 A 羧化酶抑制对 NAFLD 和肝胰岛素抵抗的影响
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乙酰辅酶A羧化酶的双重功能
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