Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease

特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估

• 批准号: 10578068
• 负责人: Rajesh H Amin
• 金额: $ 36.16万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578068
• 关键词: Adipose tissue; Age; Agonist; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease therapy; Alzheimer’s disease biomarker; Amino Acids; Amyloid; Amyloid beta-Protein; Animal Disease Models; Animals; Atherosclerosis; Behavioral; Biological Availability; Biotechnology; Blood; Blood specimen; Brain; California; Cause of Death; Cells; Cholesterol; Clinical Trials; Data; Development; Disease; Dose; Drug Kinetics; Drug Transport; Edema; Electrophysiology (science); Enzyme Induction; Esters; Evaluation; Formulation; Future; Goals; Grant; Health Care Costs; Heart; Heart failure; Hepatocyte; Hepatotoxicity; Human; In Vitro; Incidence; Intravenous; Kidney; Kinetics; LXRalpha protein; Legal patent; Lethal Dose 50; Libraries; Ligand Binding Domain; Liver; Liver X Receptor; Measurable; Measures; Medical; Memory; Memory impairment; Modeling; Molecular; Mus; Nerve Degeneration; Neuronal Plasticity; Neutropenia; Nuclear Receptors; Oral; Oral Administration; Outcome; PPAR delta; Pathology; Pathway interactions; Patients; Permeability; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Positioning Attribute; Preparation; Preventive; Public Health; Regulatory Pathway; Reporting; Research; Safety; Sampling; Skeletal Muscle; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Testing; Therapeutic; Therapeutic Agents; Tissue Sample; Tissues; Toxic effect; United States; United States National Institutes of Health; Universities; Urine; Weight; Wild Type Mouse; Work; absorption; aged; apolipoprotein E-4; blood-brain barrier crossing; design; effective therapy; efficacy testing; improved; in silico; in vitro Assay; in vivo; innovation; intraperitoneal; intravenous administration; metabolomics; mortality; mouse model; nano-string; neuroinflammation; novel; novel therapeutics; pre-clinical; programs; receptor; research and development; side effect; tau Proteins; therapeutically effective; transcriptome; treatment effect; β-amyloid burden

Project Summary Alzheimer's disease (AD) is the sixth leading cause of death in United States, yet this indication lacks truly effective therapeutics to mitigate this disease. To develop novel and effective therapies, a novel (partial) Liver-X-receptor (LXR) β and peroxisomal proliferator activating– gamma (PPARγ) nuclear receptor agonist (AU403) that has selective amino acid interactions in the receptor ligand-binding domain was developed. Preliminary data suggest AU403 may reduce AD-related pathologies, including amyloid accumulation, behavioral deficits and neurodegeneration (reduced neuronal plasticity). The goal of this current application is to further test and develop AU403 in preparation to submit an SBIR/STTR or NIH BPN program. Five aims are proposed to achieve this goal. Aim 1: Tests our in silico design that AU403 and AU403 methyl ester (me) selectively induce robust LXRβ activity. This aim will focus upon establishing EC50, LD50 and other measurable parameters of AU403 and AU403me. Aim 2 will determine the oral and IV absorption and distribution kinetics of AU403 and AU403me. The current aim will determine the minimal dose of AU403 and AU403me in the brain by lcms. The values will be compared to values in aim 1 for the EC50 for understanding the dose that induces LXRβ activity. Aim3 will evaluate the safety of AU403 in primary human hepatocytes and in vivo. We will measure in this aim the ability for AU403 to induce Liver CYP enzyme induction and expression as well as measure toxicity markers for liver and heart. Completion of the first 3 aims from the R61 portion of the grant will progress the program towards the R33 portion of the grant. The R33 portion of the grant has 2 aims which will test the efficacy of AU403 or AU403 me in the 5xFAD mouse model. Aim 4 we will test that oral administration of AU403 is efficacious in the ApoE4 x Abeta or ApoE4xTau Alzheimer's Disease animal models . This aim will determine the minimal concentration of AU403 to reduce pathology in preventative model (3-6 months in age) and Treatment model (9-12 months in age). Aim 5 will determine the impact of Au403 on neuro-energy regulatory pathways. The impact of AU403 on brain energy regulatory pathways, will be assessed by an untargeted approach to evaluate brain metabolomics in conjunction with transcriptome analysis using the Alzheimer's disease neuroinflammatory pathway. The results of these studies are expected to confirm AU403 as a potential treatment for AD and ultimately support efforts to submit an IND application and initiate Phase I clinical trials testing AU403.

项目总结

项目成果

Augmentation of Docetaxel-Induced Cytotoxicity in Human PC-3 Androgen-Independent Prostate Cancer Cells by Combination With Four Natural Apoptosis-Inducing Anticancer Compounds.

• DOI: 10.1177/1934578x231175323
• 发表时间: 2023-05
• 期刊: NATURAL PRODUCT COMMUNICATIONS
• 影响因子: 1.8
• 作者: Ahmed, Inass A.;Hafiz, Saly;van Ginkel, Sabrina;Pondugula, Satyanarayana R.;Abdelhaffez, Azza S.;Sayyed, Hayam G.;Abd El-Aziz, Ebtihal A.;Mansour, Mahmoud M.
• 通讯作者: Mansour, Mahmoud M.