Regulation of E2A in Normal and Aged B Lymphopoiesis

E2A 在正常和老年 B 淋巴细胞生成中的调节

• 批准号: 7388837
• 负责人: RICHARD L RILEY
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388837
• 关键词: Adoptive Transfer; Affect; Age; Aging; Antigen-Presenting Cells; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow; Cell Count; Cell Lineage; DNA Nucleotidylexotransferase; DNTT gene; Defect; Degradation Pathway; Development; Dissection; Gene Rearrangement; Gene Targeting; Genes; Growth and Development function; Immune; Immunofluorescence Immunologic; In Vitro; Lymphopoiesis; MAP Kinase Gene; Measures; Mediating; Messenger RNA; Modification; Molecular; Mus; Pathway interactions; Phosphorylation; Population; Proteins; Rate; Regulation; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Serine/Threonine Phosphorylation; Signal Transduction; Staging; TCF3 gene; Testing; Ubiquitin; Ubiquitination; Western Blotting; aged; base; helix-loop-helix protein E47; in vivo; multicatalytic endopeptidase complex; normal aging; notch protein; pre-B cell receptor; protein degradation; research study; senescence

DESCRIPTION (provided by applicant): The E2A gene encodes basis helix-loop-helix proteins (E47 and El2) which are crucial to the regulation of B lineage cell development within the bone marrow. E2A affects Ig gene rearrangement, proliferation, survival, and differentiation among B lymphocyte precursors. In murine senescence, B lymphocyte development is diminished and, in particular, pre-B cell numbers are generally decreased. Given the importance of E2A, we hypothesize that, in old age, expression of E2A is dysregulated during B lymphopoiesis. This may contribute to reduced B lymphopoiesis in senescence. In order to test this hypothesis, we propose three interrelated Specific Aims. In Specific Aim 1, we will assess the relative levels of expression of E2A, as both mRNA and protein, at distinct stages of B cell differentiation hi senescence in order to determine where decline hi E2A expression and/or function may occur. Specific Aim 2 asks whether transcriptional or post-transcriptional mechanisms result in reduced E2A expression in senescent B cell precursors. This Specific Aim will establish the molecular mechanisms responsible for E2A dysregulation within B cell precursors with particular emphasis on the ubiquitin-proteasome pathway. Specific Aim 3 will establish whether alterations in extrinsic (microenvironmental) signaling within the bone marrow as well as intrinsic signaling, particularly via the pre-B cell receptor, contribute to dysregulation of E2A expression hi senescent B cell precursors. The function of particular bone marrow accessory cell populations (e.g., stroma) in supporting B cell precursor growth and development in senescence will be assessed. These studies will promote understanding of the normal role of E2A hi B lymphopoiesis and the affects of E2A dysregulation on B lymphopoiesis hi senescence. More broadly, these studies will further our understanding of the immune defects which accompany old age and their cellular and molecular mechanisms.

描述（由申请人提供）：E2A基因编码基础螺旋 - 环螺旋蛋白（E47和EL2），这对于调节骨髓内B谱系细胞发育至关重要。 E2A影响B淋巴细胞前体之间的Ig基因重排，增殖，存活和分化。在鼠衰老中，B淋巴细胞发育减少，尤其是前B细胞数量通常会减少。鉴于E2A的重要性，我们假设在老年时，在B淋巴管菌中，E2a的表达失调。这可能导致衰老中的B淋巴细胞减少。为了检验这一假设，我们提出了三个相互关联的特定目的。在特定的目标1中，我们将在B细胞分化HI衰老的不同阶段评估E2a的相对水平，例如mRNA和蛋白质，以确定可能发生下降HI E2A表达和/或功能。具体目标2询问转录或转录后机制是否导致衰老B细胞前体的E2A表达降低。该特定目的将建立负责B细胞前体内E2A失调的分子机制，并特别强调泛素 - 蛋白酶体途径。具体的目标3将确定骨髓内外（微环境）信号的改变以及固有信号传导是否会导致E2A表达HI Senescent B细胞前体的失调。将评估特定的骨髓辅助细胞群（例如基质）在支持B细胞前体的生长和衰老发育中的功能。这些研究将促进对E2A HI HI淋巴管的正常作用的理解，以及E2A失调对B淋巴细胞的影响。从更广泛的角度来看，这些研究将进一步了解伴随老年及其细胞和分子机制的免疫缺陷的理解。