Our long range goal continues to be the elucidation of chromosomal organization, with emphasis on 10 chromosome fine structure and 2) three-dimensional chromosome positions in normal and abnormal interphase nuclei. We have refined and expanded non-isotopic in-situ hybridization methods toward these ends. More specifically, nucleic acids have been tagged with different ligands for simultaneous discrimination of different sequences, high resolution (ultrastructural) details have been preserved, and conditions that faithfully label single chromosome domains, or entire single chromosomes have been developed. These methods have wide application, and can be used to clarify pathogenic mechanisms in neoplastic, cytogenetic, and functionally altered human specimen. We request the opportunity to solidify and expand on our previous biological findings. Thus we will attempt 1) to further define chromosomal bands in terms of their molecular structure (e.g. SINE, Line, and other repeated DNA subsets), DNA lengths, replication patterns and structural orientation, 2) to further exploit our ability to rapidly detect complex numerical and structural aberrations in neuroectodermal tumors, and 3) to continue three-dimensional analyses of interphase chromosome position and structure in differentiating and adult CNS cells. Data from our laboratory indicates that there can be substantial and specific chromosome rearrangements in post-mitotic interphase neurons during differentiation and in pathological states (e.g. uncontrolled seizures). We suggest that such movements underlie or modulate the expression of ordered sets of genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015044-18
Application #
3164070
Study Section
Pathology A Study Section (PTHA)
Project Start
1977-12-01
Project End
1994-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
18
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Manuelidis, L (1994) Genomic stability and instability in different neuroepithelial tumors. A role for chromosome structure? J Neurooncol 18:225-39
Taruscio, D; Manuelidis, L (1991) Integration site preferences of endogenous retroviruses. Chromosoma 101:141-56
Manuelidis, L (1991) Heterochromatic features of an 11-megabase transgene in brain cells. Proc Natl Acad Sci U S A 88:1049-53
Lamperth, L; Manuelidis, L; Webster, H D (1990) P0 glycoprotein mRNA distribution in myelin-forming Schwann cells of the developing rat trigeminal ganglion. J Neurocytol 19:756-64
Manuelidis, L (1990) A view of interphase chromosomes. Science 250:1533-40
Akowitz, A; Manuelidis, L (1989) A novel cDNA/PCR strategy for efficient cloning of small amounts of undefined RNA. Gene 81:295-306
Cremer, T; Tesin, D; Hopman, A H et al. (1988) Rapid interphase and metaphase assessment of specific chromosomal changes in neuroectodermal tumor cells by in situ hybridization with chemically modified DNA probes. Exp Cell Res 176:199-220
Borden, J; Manuelidis, L (1988) Movement of the X chromosome in epilepsy. Science 242:1687-91
Lichter, P; Cremer, T; Tang, C J et al. (1988) Rapid detection of human chromosome 21 aberrations by in situ hybridization. Proc Natl Acad Sci U S A 85:9664-8
Cremer, T; Lichter, P; Borden, J et al. (1988) Detection of chromosome aberrations in metaphase and interphase tumor cells by in situ hybridization using chromosome-specific library probes. Hum Genet 80:235-46

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