WO1997028825A2 - Spermatogenesis control - Google Patents

Spermatogenesis control Download PDF

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Publication number
WO1997028825A2
WO1997028825A2 PCT/DE1997/000245 DE9700245W WO9728825A2 WO 1997028825 A2 WO1997028825 A2 WO 1997028825A2 DE 9700245 W DE9700245 W DE 9700245W WO 9728825 A2 WO9728825 A2 WO 9728825A2
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WO
WIPO (PCT)
Prior art keywords
crem
compound
spermatogenesis
dependent proteins
pharmaceutical composition
Prior art date
Application number
PCT/DE1997/000245
Other languages
German (de)
French (fr)
Other versions
WO1997028825A3 (en
Inventor
Günther Schütz
Julie A. Blendy
Klaus KÄSTNER
Gerhard Weinbauer
Eberhard Nieschlag
Original Assignee
Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to JP9528059A priority Critical patent/JP2000505893A/en
Priority to EP97915278A priority patent/EP0879061A2/en
Publication of WO1997028825A2 publication Critical patent/WO1997028825A2/en
Publication of WO1997028825A3 publication Critical patent/WO1997028825A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives

Definitions

  • the present invention relates to a pharmaceutical composition for regulating spermatogenesis and a method for examining spermatogenesis, as well as a kit that can be used for this.
  • spermatogenesis is the development of sperm. Intervention in spermatogenesis is desirable if it is disturbed and does not lead to functional sperm. On the other hand, intervention in spermatogenesis could also be used to carry out a fertility check in men.
  • the present invention is therefore based on the object of providing a means by which spermatogenesis can be regulated.
  • the present invention thus relates to a pharmaceutical composition which is suitable for regulating spermatogenesis.
  • a pharmaceutical composition which is suitable for regulating spermatogenesis.
  • Such a composition includes:
  • CREM a CREM-phosphorylating compound and an expression of CREM-inducing compound, and / or
  • CREM cAMP responsive element modulator
  • CREM-dependent proteins examples of such are proacrosine, protamine, Tp-1 (transision protein-1) MCS (mitochondrial capsule seleno protein) and RT7 (mill germ cell specific protein). If there is a CREM deficiency, i.e. if CREM is not or only partially or not expressed in phosphorylated form, whereby the above proteins are also not or only partially expressed, there is a disturbed spermatogenesis which leads to inoperable sperm.
  • the expression “a CREM phosphorylating compound” relates to any compounds suitable for phosphorylating CREM, in particular kinases.
  • the expression “a compound inducing the expression of CREM” relates to any compounds which can directly or indirectly induce the expression of CREM.
  • the expression “a CREM-inhibiting compound” relates to any compounds suitable for inhibiting CREM, in particular to antibodies directed against CREM.
  • the term “a compound that inhibits phosphorylation of CREM” refers to any compound that is useful for inhibiting phosphorylation of CREM.
  • Such compounds are in particular kinase inhibitors such as H7, H8, H89, HA 1004 and Walsh inhibitor.
  • the expression “a compound which inhibits the expression of CREM” relates to any compounds which can directly or indirectly inhibit the expression of CREM.
  • the person skilled in the art knows how to determine which of the substances mentioned for a pharmaceutical composition of the present invention and which amounts are best suited for spermatogenesis regulation in a single subject.
  • a transgenic mouse which expresses an inducible CREB (cyclic AMP responsive element binding protein) mutant in round spermatids of the testis. This mutant dimerizes with CREM, the mutant being dominant-negative compared to CREM, ie CREM is inhibited by dimerization with dominant-negative CREB.
  • the transgenic mouse therefore enables the determination of substances and their quantities that have an influence on CREM and thus on spermatogenesis.
  • a vector into fertilized egg cells of a mouse which promoter enables gene expression in round spermatozoa, such as the protamine promoter (cf. Zambrowicz, BP et al., Proc. Natl. Acad USA 90, (1 990), 5071-5075).
  • This promoter is under the control of a DNA which codes for a fusion protein from the mutated CREB and an altered ligand binding domain of the human progesterone receptor (cf. Wang, Y, et al., Proc. Natl. Acad. Sci. USA 91, ( 1 994), 8180-8184).
  • the mutated CREB at position 1 33 does not have serine but alanine and therefore cannot be phosphorylated, which means the loss of its transcription activity.
  • Amino acids 892-933 are missing in the modified ligand-binding domain of the human progesterone receptor, which means that this ligand-binding domain can no longer be bound by progesterone but only by the ligand RU 486.
  • the mutant CREB is activated in the fusion protein by the latter.
  • a method is also provided which is suitable for examining or monitoring spermatogenesis.
  • One such method involves the determination of CREM and / or CREM dependent proteins, e.g. Proacrosine, Protamine, Tp-1, MCS and RT7.
  • CREM and / or CREM-dependent proteins For the determination of CREM and / or CREM-dependent proteins usual methods are used. It is advantageous to use PCR methods to determine whether the DNA sequences coding for CREM and / or CREM-dependent proteins have mutations. Furthermore, it is advisable to puncture the testes in order to examine preferably spermatids and particularly preferably round spermatids of testes and to determine the expression of CREM and / or CREM-dependent proteins.
  • CREM and / or CREM-dependent proteins can be determined in a Western blot analysis, in which antibodies against the individual proteins are used. The mRNA of CREM and / or CREM-dependent proteins can also be determined in a Northerner blot analysis in which DNAs of the individual proteins are used as samples.
  • kits which is suitable for the determination of CREM and / or CREM-dependent proteins.
  • a kit includes:
  • spermatogenesis ie to positively regulate a disturbed spermatogenesis, as a result of which functional spermatozoa are formed, and to negatively regulate normal spermatogenesis, as a result of which sperm formation is inhibited.
  • the regulation of spermatogenesis is reversible, making the negative regulation particularly suitable for controlling the fertility of a male animal, especially a male.

Abstract

The present invention relates to a pharmaceutical composition comprising: (a) for positive control, one or more substances of cAMP responsive element modulator (CREM), a CREM phosphorylating compound and a CREM expression inducing compound, and/or (b) for negative control, one or more substances of a CREM-inhibiting compound, a CREM phosphorylating inhibiting compound and a CREM expression inhibiting compound. The invention also relates to a process for investigating spermatogenesis and a kit usable therefor.

Description

Regulierung der Spermatogenese Regulation of spermatogenesis
Die vorliegende Erfindung betrifft eine pharmazeutische Zusammensetzung zur Regulierung der Spermatogenese und ein Verfahren zur Untersuchung der Spermatogenese sowie einen hierfür verwendbaren Kit.The present invention relates to a pharmaceutical composition for regulating spermatogenesis and a method for examining spermatogenesis, as well as a kit that can be used for this.
Mit Spermatogenese wird die Entwicklung von Spermien bezeichnet. Ein Ein¬ greifen in die Spermatogenese ist wünschenswert, wenn sie gestört ist und nicht zu funktionsfähigen Spermien führt. Andererseits könnte ein Eingreifen in die Spermatogenese auch genutzt werden, um eine Fertilitätskontrolle beim Mann durchzuführen.Spermatogenesis is the development of sperm. Intervention in spermatogenesis is desirable if it is disturbed and does not lead to functional sperm. On the other hand, intervention in spermatogenesis could also be used to carry out a fertility check in men.
Der vorliegenden Erfindung liegt somit die Aufgabe zugrunde, ein Mittel bereitzu¬ stellen, mit dem die Spermatogenese reguliert werden kann.The present invention is therefore based on the object of providing a means by which spermatogenesis can be regulated.
Erfindungsgemäß wird dies durch die Gegenständige in den Patentansprüchen erreicht.According to the invention, this is achieved by the subject-matter in the claims.
Gegenstand der vorliegenden Erfindung ist somit eine pharmazeutische Zusam¬ mensetzung, die sich zur Regulierung der Spermatogenese eignet. Eine solche Zusammensetzung umfaßt:The present invention thus relates to a pharmaceutical composition which is suitable for regulating spermatogenesis. Such a composition includes:
(a) zur positiven Regulierung ein oder mehr Stoffe von(a) for positive regulation one or more substances of
CREM, einer CREM-phosphorylierenden Verbindung und einer die Ex¬ pression von CREM induzierenden Verbindung, und/oderCREM, a CREM-phosphorylating compound and an expression of CREM-inducing compound, and / or
(b) zur negativen Regulierung ein oder mehr Stoffe von einer CREM-hemmenden Verbindung, einer die Phosphorylierung von CREM hemmenden Verbindung und einer die Expression von CREM hem¬ menden Verbindung.(b) to negatively regulate one or more substances from an CREM-inhibiting compound, one which inhibits the phosphorylation of CREM-inhibiting compound and a CREM-inhibiting compound.
Die vorliegende Erfindung beruht auf der Erkenntnis des Anmelders, daß CREM (cAMP responsive element modulator) ein entscheidender Regulator der Sperma¬ togenese ist. Der Anmelder hat gefunden, daß CREM ein Transkriptionsfaktor ist, der die Expression von an der Spermatogenese beteiligten Proteinen kon¬ trolliert. Diese Proteine werden in der vorliegenden Anmeldung als CREM-ab- hängige Proteine bezeichnet. Beispiele solcher sind Proacrosin, Protamin, Tp-1 (transision protein- 1 ) MCS (mitochondrial capsule seleno protein) und RT7 (mill germ cell specific protein). Findet sich eine CREM-Defizienz, d.h. ist CREM nicht oder nur vermindert bzw. nicht in phosphorylierter Form exprimiert, wodurch vorstehende Proteine ebenfalls nicht oder nur vermindert exprimiert sind, liegt eine gestörte Spermatogenese vor, die zu funktionsunfähigen Spermien führt.The present invention is based on the knowledge of the applicant that CREM (cAMP responsive element modulator) is a crucial regulator of sperm togenesis. The applicant has found that CREM is a transcription factor that controls the expression of proteins involved in spermatogenesis. In the present application, these proteins are referred to as CREM-dependent proteins. Examples of such are proacrosine, protamine, Tp-1 (transision protein-1) MCS (mitochondrial capsule seleno protein) and RT7 (mill germ cell specific protein). If there is a CREM deficiency, i.e. if CREM is not or only partially or not expressed in phosphorylated form, whereby the above proteins are also not or only partially expressed, there is a disturbed spermatogenesis which leads to inoperable sperm.
In einer pharmazeutischen Zusammensetzung der vorliegenden Erfindung betrifft der Ausdruck "eine CREM-phosphorylierende Verbindung" jegliche zur Phospho¬ rylierung von CREM geeignete Verbindungen, insbesondere Kinasen. Ferner betrifft der Ausdruck "eine die Expression von CREM induzierende Verbindung" jegliche Verbindungen, die direkt oder indirekt die Expression von CREM induzie¬ ren können. Desweiteren betrifft der Ausdruck "eine CREM-hemmende Ver¬ bindung" jegliche zur Hemmung von CREM geeignete Verbindungen, insbesonde¬ re gegen CREM-gerichtete Antikörper. Darüberhinaus betrifft der Ausdruck "eine die Phosphorylierung von CREM hemmende Verbindung" jegliche Verbindungen, die zur Hemmung der Phosphorylierung von CREM geeignet sind. Solche Ver¬ bindungen sind insbesondere Kinase-Inhibitoren, wie H7, H8, H89, HA 1004 und Walsh-Inhibitor. Weiterhin betrifft der Ausdruck "eine die Expression von CREM hemmende Verbindung" jegliche Verbindungen, die direkt oder indirekt die Expression von CREM hemmen können.In a pharmaceutical composition of the present invention, the expression “a CREM phosphorylating compound” relates to any compounds suitable for phosphorylating CREM, in particular kinases. Furthermore, the expression “a compound inducing the expression of CREM” relates to any compounds which can directly or indirectly induce the expression of CREM. Furthermore, the expression “a CREM-inhibiting compound” relates to any compounds suitable for inhibiting CREM, in particular to antibodies directed against CREM. In addition, the term "a compound that inhibits phosphorylation of CREM" refers to any compound that is useful for inhibiting phosphorylation of CREM. Such compounds are in particular kinase inhibitors such as H7, H8, H89, HA 1004 and Walsh inhibitor. Furthermore, the expression “a compound which inhibits the expression of CREM” relates to any compounds which can directly or indirectly inhibit the expression of CREM.
Der Fachmann weiß, wie er bestimmen kann, welche der für eine pharmazeuti¬ sche Zusammensetzung der vorliegenden Erfindung genannten Stoffe und welche Mengen davon sich für die Spermatogenese-Regulierung bei einem einzelnen Probanden am besten eignen. Für den Fachmann bietet sich z.B. folgendes an: Herstellung einer transgenen Maus, die in runden Spermatiden des Hodens eine induzierbare CREB (cyclic AMP responsive element binding protein)- Mutante exprimiert. Diese Mutante dimerisiert mit CREM, wobei die Mutante gegenüber CREM dominant-negativ ist, d.h. CREM wird durch Dimerisierung mit dominant-negativem CREB inhibiert. Die transgene Maus ermöglicht daher die Bestimmung von Stoffen und deren Mengen, die Einfluß auf CREM und somit auf die Spermatogenese haben.The person skilled in the art knows how to determine which of the substances mentioned for a pharmaceutical composition of the present invention and which amounts are best suited for spermatogenesis regulation in a single subject. For the person skilled in the art there are, for example, the following: Production of a transgenic mouse which expresses an inducible CREB (cyclic AMP responsive element binding protein) mutant in round spermatids of the testis. This mutant dimerizes with CREM, the mutant being dominant-negative compared to CREM, ie CREM is inhibited by dimerization with dominant-negative CREB. The transgenic mouse therefore enables the determination of substances and their quantities that have an influence on CREM and thus on spermatogenesis.
Zur Herstellung der transgenen Maus bietet sich an, in befruchtete Eizellen einer Maus einen Vektor einzuführen, der einen die Genexpression in runden Spermati¬ den ermöglichenden Promotor, wie den Protamin-Promotor (vgl. Zambrowicz, B.P. et al., Proc. Natl. Acad. Sei. USA 90, ( 1 990), 5071 -5075) , enthält. Unter der Kontrolle dieses Promotors steht eine DNA, die für ein Fusionsprotein aus dem mutierten CREB und einer veränderten Liganden-Bindungsdomäne des menschlichen Progesteronrezeptors kodiert (vgl. Wang, Y, et al., Proc. Natl. Acad. Sei. USA 91 , (1 994), 8180-8184). Das mutierte CREB weist an der Position 1 33 nicht Serin sondern Alanin auf und kann daher nicht phosphoryliert werden, was den Verlust seiner Transkriptionsaktivität bedeutet. In der ver¬ änderten Liganden-Bindungsdomäne des menschlichen Progesteronrezeptors fehlen die Aminosäuren 892-933, wodurch diese Liganden-Bindungsdomäne nicht mehr durch Progesteron sondern nur noch durch den Liganden RU 486 gebunden werden kann. Durch letzteren wird das mutierte CREB im Fusions¬ protein aktiviert.For the production of the transgenic mouse, it is advisable to insert a vector into fertilized egg cells of a mouse which promoter enables gene expression in round spermatozoa, such as the protamine promoter (cf. Zambrowicz, BP et al., Proc. Natl. Acad USA 90, (1 990), 5071-5075). This promoter is under the control of a DNA which codes for a fusion protein from the mutated CREB and an altered ligand binding domain of the human progesterone receptor (cf. Wang, Y, et al., Proc. Natl. Acad. Sci. USA 91, ( 1 994), 8180-8184). The mutated CREB at position 1 33 does not have serine but alanine and therefore cannot be phosphorylated, which means the loss of its transcription activity. Amino acids 892-933 are missing in the modified ligand-binding domain of the human progesterone receptor, which means that this ligand-binding domain can no longer be bound by progesterone but only by the ligand RU 486. The mutant CREB is activated in the fusion protein by the latter.
Erfindungsgemäß wird auch ein Verfahren bereitgestellt, das sich zur Unter¬ suchung bzw. Überwachung der Spermatogenese eignet. Ein solches Verfahren umfaßt die Bestimmung von CREM und/oder CREM-abhängigen Proteinen, z.B. Proacrosin, Protamin, Tp-1 , MCS und RT7.According to the invention, a method is also provided which is suitable for examining or monitoring spermatogenesis. One such method involves the determination of CREM and / or CREM dependent proteins, e.g. Proacrosine, Protamine, Tp-1, MCS and RT7.
Für die Bestimmung von CREM und/oder CREM-abhängigen Proteinen können übliche Verfahren verwendet werden. Günstig ist es, mittels PCR-Verfahren zu bestimmen, ob die für CREM und/oder CREM-abhängige Proteine kodierenden DNA-Sequenzen Mutationen aufweisen. Ferner bietet sich an, Punktionen am Hoden durchzuführen, um bevorzugt Spermatiden und besonders bevorzugt runde Spermatiden von Hoden zu untersuchen und die Expression von CREM und/oder CREM-abhängigen Proteinen zu bestimmen. Hierfür können CREM und/oder CREM-abhängige Proteine in einer Western-Blot-Analyse bestimmt werden, in der Antikörper gegen die einzelnen Proteine verwendet werden. Auch kann die mRNA von CREM und/oder CREM-abhängigen Proteinen in einer Nort- hern-Blot-Analyse bestimmt werden, in der DNAs der einzelnen Proteine als Proben verwendet werden.For the determination of CREM and / or CREM-dependent proteins usual methods are used. It is advantageous to use PCR methods to determine whether the DNA sequences coding for CREM and / or CREM-dependent proteins have mutations. Furthermore, it is advisable to puncture the testes in order to examine preferably spermatids and particularly preferably round spermatids of testes and to determine the expression of CREM and / or CREM-dependent proteins. For this purpose, CREM and / or CREM-dependent proteins can be determined in a Western blot analysis, in which antibodies against the individual proteins are used. The mRNA of CREM and / or CREM-dependent proteins can also be determined in a Northerner blot analysis in which DNAs of the individual proteins are used as samples.
Erfindungsgemäß wird auch ein Kit bereitgestellt, der zur Bestimmung von CREM und/oder CREM-abhängigen Proteinen geeignet ist. Ein solcher Kit umfaßt:According to the invention, a kit is also provided which is suitable for the determination of CREM and / or CREM-dependent proteins. Such a kit includes:
ein oder mehr von (a) - (c)one or more of (a) - (c)
(a) Primer für eine Amplifikation von für CREM- und oder CREM-abhängigen Proteinen kodierender DNA,(a) primer for an amplification of DNA coding for CREM- and or CREM-dependent proteins,
(b) Antikörper gegen CREM und/oder CREM-abhängige Proteine, z.B. Proacro- sin, Protamin, Tp-1 , MCS und RT7,(b) Antibodies to CREM and / or CREM dependent proteins, e.g. Proacrosin, Protamin, Tp-1, MCS and RT7,
(c) DNA-Proben für mRNA von CREM und/oder CREM-abhängigen Proteinen, z.B. Proacrosin, Protamin, Tp-1 , MCS und RT7, sowie(c) DNA samples for mRNA from CREM and / or CREM dependent proteins, e.g. Proacrosine, Protamine, Tp-1, MCS and RT7, as well
(d) Standards und Nachweisreagentien für ein oder mehr von (a) - (c), und(d) standards and detection reagents for one or more of (a) - (c), and
(e) Träger sowie übliche Hilfsstoffe.(e) carriers and customary auxiliaries.
Mit der vorliegenden Erfindung ist es möglich, die Spermatogenese zu regulieren, d.h. eine gestörte Spermatogenese positiv zu regulieren, wodurch funktions¬ fähige Spermien gebildet werden, und eine normale Spermatogenese negativ zu regulieren, wodurch die Spermienbildung gehemmt wird. Die Regulierung der Spermatogenese ist reversibel, wodurch sich die negative Regulierung besonders zur Kontrolle der Fertilität eines männlichen Tieres, insbesondere des Mannes, eignet. Mit der vorliegenden Erfindung ist es ferner möglich, die Spermatogenese zu überwachen, was insbesondere wichtig ist, wenn regulierend eingegriffen worden ist. With the present invention it is possible to regulate spermatogenesis, ie to positively regulate a disturbed spermatogenesis, as a result of which functional spermatozoa are formed, and to negatively regulate normal spermatogenesis, as a result of which sperm formation is inhibited. The regulation of spermatogenesis is reversible, making the negative regulation particularly suitable for controlling the fertility of a male animal, especially a male. With the present invention, it is also possible to monitor spermatogenesis, which is particularly important when regulatory intervention has been carried out.

Claims

Patentansprüche claims
1 . Pharmazeutische Zusammensetzung, geeignet zur Regulierung der Sper¬ matogenese, umfassend:1 . A pharmaceutical composition suitable for regulating spermatogenesis, comprising:
(a) zur positiven Regulierung ein oder mehr Stoffe von(a) for positive regulation one or more substances of
CREM, einer CREM-phosphorylierenden Verbindung und einer die Expression von CREM-induzierenden Verbindung, und/oderCREM, a CREM-phosphorylating compound and an expression of CREM-inducing compound, and / or
(b) zur negativen Regulierung ein oder mehr Stoffe von einer CREM-hemmenden Verbindung, einer die Phosphorylierung von CREM hemmenden Verbindung und einer die Expression von CREM hemmenden Verbindung.(b) for negative regulation of one or more substances of a CREM-inhibiting compound, a phosphorylation of CREM-inhibiting compound and a CREM-inhibiting compound.
2. Pharmazeutische Zusammensetzung nach Anspruch 1 , dadurch gekenn¬ zeichnet, daß die CREM-phosphorylierende Verbindung eine Kinase ist, und die die Phosphorylierung von CREM hemmende Verbindung ein Kinase-Inhibitor ist.2. Pharmaceutical composition according to claim 1, characterized gekenn¬ characterized in that the CREM-phosphorylating compound is a kinase, and the compound inhibiting phosphorylation of CREM is a kinase inhibitor.
3. Verfahren zur Untersuchung bzw. Überwachung der Spermatogenese, wobei CREM und/oder CREM-abhängige Proteine bestimmt werden.3. Method for examining or monitoring spermatogenesis, whereby CREM and / or CREM-dependent proteins are determined.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß die CREM- abhängigen Proteine Proacrosin, Protamin, Tp-1 , MCS und/oder RT7 sind.4. The method according to claim 3, characterized in that the CREM-dependent proteins are proacrosine, protamine, Tp-1, MCS and / or RT7.
5. Kit zur Durchführung des Verfahrens nach Anspruch 3 oder 4, umfassend ein oder mehr von (a) - (c) (a) Primer für eine Amplifikation von für CREM- und/oder CREM-ab¬ hängigen Proteinen kodierende DNA,5. Kit for performing the method according to claim 3 or 4, comprising one or more of (a) - (c) (a) primer for an amplification of DNA coding for CREM- and / or CREM-dependent proteins,
(b) Antikörper gegen CREM und/oder CREM-abhängige Proteine,(b) antibodies against CREM and / or CREM-dependent proteins,
(c) DNA-Proben für mRNA von CREM und/oder CREM-abhängigen Proteinen, sowie(c) DNA samples for mRNA of CREM and / or CREM-dependent proteins, as well
(d) Standards und Nachweisreagentien für ein oder mehr von (a) - (c), und(d) standards and detection reagents for one or more of (a) - (c), and
(e) Träger sowie übliche Hilfsstoffe.(e) carriers and customary auxiliaries.
6. Kit nach Anspruch 5, adurch gekennzeichnet, daß die CREM-abhängigen Proteine Proacrosin, Protamin, Tp-1 , MCS und/oder RT7 sind.6. Kit according to claim 5, characterized in that the CREM-dependent proteins are proacrosine, protamine, Tp-1, MCS and / or RT7.
7. Verwendung von (b) der pharmazeutischen Zusammensetzung nach Anspruch 1 oder 2 zur Fertilitätskontrolle beim Mann. 7. Use of (b) the pharmaceutical composition according to claim 1 or 2 for fertility control in men.
PCT/DE1997/000245 1996-02-09 1997-02-10 Spermatogenesis control WO1997028825A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP9528059A JP2000505893A (en) 1996-02-09 1997-02-10 Spermatogenesis control
EP97915278A EP0879061A2 (en) 1996-02-09 1997-02-10 Spermatogenesis control

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Application Number Priority Date Filing Date Title
DE19604773A DE19604773A1 (en) 1996-02-09 1996-02-09 Regulation of spermatogenesis
DE19604773.0 1996-02-09

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WO1997028825A2 true WO1997028825A2 (en) 1997-08-14
WO1997028825A3 WO1997028825A3 (en) 1997-10-02

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Publication number Priority date Publication date Assignee Title
EP1211313A2 (en) * 2000-11-01 2002-06-05 Pfizer Limited Modulation of PDE11A activity
US6828473B2 (en) 2000-11-01 2004-12-07 Pfizer Inc. Modulation of PDE11A activity

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JP4875026B2 (en) * 2008-06-30 2012-02-15 全国農業協同組合連合会 Sperm motility activator and sperm activation method

Non-Patent Citations (2)

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Title
BIOLOGY OF REPRODUCTION, 50 (4). 1994. 869-881., XP000677640 WEST A P ET AL: "Differential regulation of cyclic adenosine 3',5'-monophosphate (cAMP) response element-binding protein and cAMP response element modulator messenger ribonucleic acid transcripts by follicle-stimulating hormone and androgen in the adult rat testis" *
MOLECULAR ENDOCRINOLOGY, 7 (11). 1993. 1502-1514., XP002036608 DELMAS V ET AL: "Induction of CREM activator proteins in spermatids: Down-stream targets and implications for haploid germ cell differentiation" *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1211313A2 (en) * 2000-11-01 2002-06-05 Pfizer Limited Modulation of PDE11A activity
EP1211313A3 (en) * 2000-11-01 2003-04-23 Pfizer Limited Modulation of PDE11A activity
US6828473B2 (en) 2000-11-01 2004-12-07 Pfizer Inc. Modulation of PDE11A activity

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WO1997028825A3 (en) 1997-10-02
EP0879061A2 (en) 1998-11-25
DE19604773A1 (en) 1997-08-14

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