Blood coagulation activity in the normal human population elevates with advancing age. When combined with age-dependent disorders like atherosclerosis, this increase in the coagulation potential may play a role in the increased frequency of cardiovascular and thrombotic disorders in the elderly. Presently, little is known about the molecular mechanisms responsible for this phenomenon and homeostasis of the coagulation system in general. The long-term goal of this proposal is to determine the molecular mechanisms underlying age-dependent regulation and homeostasis of the blood coagulation system. The factor IX gene will serve as an initial model gene for intensive studies. Recently the applicant has identified two major activities associated with specific regions of the factor IX gene that are essential for age-dependent regulation of expression. This proposal has five specific aims.
Specific Aim 1 is to establish the mechanisms of action of two cis-acting elements, AE5' (a PEA3 binding element) and AE3' (a sequence containing extensive dinucleotide repeats) in age-dependent regulation of the human factor IX gene.
Specific Aim 2 is to delineate the switch mechanisms in expression of transcriptional factors over the puberty period.
Specific Aim 3 is to identify potential additional gene structures with modifying activities on age-dependent regulation of the gene.
Specific Aim 4 is to determine the physiological significance of advancing age-dependent elevation in factor IX gene expression by constructing a mouse model lacking such elevation in the endogenous mouse factor IX gene.
Specific Aim 5 is to determine the biological significance of elevated or lowered plasma factor IX levels in relation to age. The molecular mechanisms established for the factor IX gene will facilitate subsequent studies on other key coagulation factors and regulators, laying the foundation for comprehensive understanding of the overall age-dependent regulation (homeostasis) of the coagulation system. Such knowledge may help develop novel and/or improved treatments for hemorrhagic disorders as well as thrombotic and cardiovascular diseases in the elderly.
| Kurachi, Sumiko; Huo, Jeffrey S; Ameri, Afshin et al. (2009) An age-related homeostasis mechanism is essential for spontaneous amelioration of hemophilia B Leyden. Proc Natl Acad Sci U S A 106:7921-6 |
| Ameri, Afshin; Kurachi, Sumiko; Sueishi, Katsuo et al. (2003) Myocardial fibrosis in mice with overexpression of human blood coagulation factor IX. Blood 101:1871-3 |
| Zhang, Kezhong; Kurachi, Sumiko; Kurachi, Kotoku (2003) Limitation in use of heterologous reporter genes for gene promoter analysis. Silencer activity associated with the cloramphenicol acetyltransferase reporter gene. J Biol Chem 278:4826-30 |
| Zhang, Kezhong; Kurachi, Sumiko; Kurachi, Kotoku (2002) New function for age-related stability element in conferring strict tissue-specific expression of human factor IX and protein C genes. Thromb Haemost 88:537-8 |
| Zhang, Kezhong; Kurachi, Sumiko; Kurachi, Kotoku (2002) Genetic mechanisms of age regulation of protein C and blood coagulation. J Biol Chem 277:4532-40 |
