Role of IPMK in generation of small intestinal carcinoid

IPMK在小肠类癌生成中的作用

• 批准号: 10630648
• 负责人: Prasun Guha
• 金额: $ 35.67万
• 依托单位: UNIVERSITY OF NEVADA LAS VEGAS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630648
• 关键词: Affect; Amino Acids; Apoptosis; Base Pairing; Binding Sites; Biochemical; Biological; C-terminal; Carcinoid Tumor; Cell Cycle Arrest; Cell Cycle Regulation; Cell Nucleus; Cell Proliferation; Cells; Centers of Research Excellence; Clinical; Cre lox recombination system; Deletion Mutation; Development; Enzymes; Epithelial Cells; Exhibits; Gene Dosage; Generations; Genes; Genetic; Genetic Transcription; Homo; Impairment; Inositol; Intestinal Cancer; Intestinal Neuroendocrine Neoplasm; Knockout Mice; Length; Link; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Mus; Mutation; Nevada; Nuclear; Nuclear Localization Signal; Operative Surgical Procedures; Pathway interactions; Patients; Phosphotransferases; Primary Neoplasm; Prognosis; Proteins; Reporting; Role; Serotonin; Signal Transduction; Small Intestines; TP53 gene; advanced disease; age related; common treatment; inositol polyphosphate multikinase; intestinal epithelium; intestinal homeostasis; loss of function; mutant; personalized medicine; tumor

Serotonin secreting small intestinal neuroendocrine tumors (SI-NET) are primary malignancies of the small bowel. When clinically recognized, afflicted patients often present with advanced disease and a poor 5-year prognosis (~36%). Surgery is the most common treatment of SI-NET. The genetic basis of Familial SI-NET is distinct from sporadic SI-NET. The only reported mutation linked to familial SI-NET is four base pair deletion mutations in the IPMK (Inositol polyphosphate multikinase) gene. IPMK protein is 416 amino acids in length,and the mutation truncates it to 333, eliminating the C-terminal ATP binding site and partial nuclear localization signal. IPMK heterozygous mutation exhibits a reduction of its kinase activity and nuclear localization. IPMK is the rate-limiting enzyme in the higher-order inositol synthesis pathway and generates inositol penta-phosphate. In mammalian cells, IPMK also acts as a PI3kinase. IPMK is primarily enriched in the nucleus, and loss of function of IPMK impairs p53 mediated transcription. As loss of p53 function is highly linked to several intestinal cancers, we like to investigate the importance of IPMK mutant (found in SI-NET patients) in p53 mediated apoptosis or cell cycle arrest in the origination of malignancies and tumor formation. How, homozygous loss of function of IPMK and a heterozygous mutant form of IPMK impair p53 mediated apoptosis and cell cycle arrest is entirely unknown and worth investigating to understand the molecular mechanism of SI-NET origination. Using Cre-Lox technology, we developed an intestinal epithelial cell-specific IPMK conditional homo and heterozygous KO mouse to understand the mechanism of IPMK mediated SI-NET development. We propose three specific aims—Aim 1. Determine how IPMK gene dosage affects the extent of SI-NET in mice. The histo-pathological, immuno-histochemical, and biochemical analysis will be performed to understand how hetero and homozygous loss of IPMK affects intestinal homeostasis and the extent of SI-NET generation in an age dependent manner. Aim 2. To determine if IPMK is necessary and sufficient to enhance cell proliferation and cell cycle regulation. Cell biological and flow-cytometric analysis will be performed to understand the critical function of IPMK in regulating cell proliferation and apoptosis. Aim 3. Determine if p53 is necessary for IPMK signaling-induced apoptosis and cell cycle arrest.

血清素分泌性小肠神经内分泌肿瘤（SI-NET）是小肠的原发性恶性肿瘤